# Patent

## Title
N-sulfonylated pyrazolo[3,4-b]pyridin-6-carboxamides and method of use

## Abstract

The present invention provides for compounds of formula (I)




wherein R1, R2, R3, R4, R5, and R6 have any of the values defined in the specification, and pharmaceutically acceptable salts thereof, that are useful as agents in the treatment of diseases and conditions mediated and modulated by CFTR, including cystic fibrosis, Sjögren's syndrome, pancreatic insufficiency, chronic obstructive lung disease, and chronic obstructive airway disease. Also provided are pharmaceutical compositions comprised of one or more compounds of formula (I).

## Background
CROSS REFERENCE TO RELATED APPLICATIONS
This application claims priority to U.S. Provisional Application No. 62/239,647, filed Oct. 9, 2015 and U.S. Provisional Application No. 62/309,794, filed Mar. 17, 2016, both of which are incorporated herein by reference for all purposes.


BACKGROUND OF THE INVENTION
Technical Field
The invention relates to compounds that are modulators of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein, useful in treating diseases and conditions mediated and modulated by CFTR. Additionally, the invention relates to compositions containing compounds of the invention and processes for their preparation.
Description of Related Technology
ATP-Binding Cassette (“ABC”) transporters are a family of homologous membrane transporter proteins regulating the transport of a wide variety of pharmacological agents (for example drugs, xenobiotics, anions, etc.) that bind and use cellular adenosine triphosphate (ATP) for their specific activities. Some of these transporters were found to defend malignant cancer cells against chemotherapeutic agents, acting as multidrug resistance proteins (like the MDR1-P glycoprotein, or the multidrug resistance protein, MRP 1). So far, 48 ABC transporters, grouped into 7 families based on their sequence identity and function, have been identified.
ABC transporters provide protection against harmful environmental compounds by regulating a variety of important physiological roles within the body, and therefore represent important potential drug targets for the treatment of diseases associated with transporter defects, outwards cell drug transport, and other diseases in which modulation of ABC transporter activity may be beneficial.
The cAMP/ATP-mediated anion channel, CFTR, is one member of the ABC transporter family commonly associated with diseases, which is expressed in a variety of cell types, including absorptive and secretory epithelia cells, where it regulates anion flux across the membrane, as well as the activity of other ion channels and proteins. The activity of CFTR in epithelial cells is essential for the maintenance of electrolyte transport throughout the body, including respiratory and digestive tissue (Quinton, P. M., 1990. Cystic fibrosis: a disease in electrolyte transport. FASEB J. 4, 2709-2717).
The gene encoding CFTR has been identified and sequenced (Kerem, B., Rommens, J. M., Buchanan, J. A., Markiewicz, D., Cox, T. K., Chakravarti, A., Buchwald, M., Tsui, L. C., 1989. Identification of the cystic fibrosis gene: genetic analysis. Science 245, 1073-1080). CFTR comprises about 1480 amino acids that encode a protein made up of a tandem repeat of transmembrane domains, each containing six transmembrane helices and a nucleotide binding domain. The pair of transmembrane domains is linked by a large, polar, regulatory (R)-domain with multiple phosphorylation sites that regulate channel activity and cellular trafficking.
Cystic fibrosis is (CF) caused by a defect in this gene which induces mutations in CFTR. Cystic fibrosis is the most common fatal genetic disease in humans and affects  ̃0.04% of white individuals (Bobadilla, J. L., Macek, M., Jr, Fine, J. P., Farrell, P. M., 2002. Cystic fibrosis: a worldwide analysis of CFTR mutations—correlation with incidence data and application to screening. Hum. Mutat. 19, 575-606. doi:10.1002/humu.10041), for example, in the United States, about one in every 2,500 infants is affected, and up to 10 million people carry a single copy of the defective gene without apparent ill effects; moreover subjects bearing a single copy of the gene exhibit increased resistance to cholera and to dehydration resulting from diarrhea. This effect might explain the relatively high frequency of the CF gene within the population.
In contrast, individuals with two copies of the CF associated gene suffer from the debilitating and fatal effects of CF, including chronic lung infections.
In cystic fibrosis patients, mutations in endogenous respiratory epithelial CFTR fail to confer chloride and bicarbonate permeability to epithelial cells in lung and other tissues, thus leading to reduced apical anion secretion and disruptions of the ion and fluid transport. This decrease in anion transport causes an enhanced mucus and pathogenic agent accumulation in the lung triggering microbial infections that ultimately cause death in CF patients.
Beyond respiratory disease, CF patients also suffer from gastrointestinal problems and pancreatic insufficiency that result in death if left untreated. Furthermore, female subjects with cystic fibrosis suffer from decreased fertility, whilst males with cystic fibrosis are infertile.
A variety of disease causing mutations have been identified through sequence analysis of the CFTR gene of CF chromosomes (Kerem, B., Rommens, J. M., Buchanan, J. A., Markiewicz, D., Cox, T. K., Chakravarti, A., Buchwald, M., Tsui, L. C., 1989. Identification of the cystic fibrosis gene: genetic analysis. Science 245, 1073-1080). ΔF508-CFTR, the most common CF mutation (present in at least 1 allele in  ̃90% of CF patients) and occurring in approximately 70% of the cases of cystic fibrosis, contains a single amino acid deletion of phenylalanine 508. This deletion prevents the nascent protein from folding correctly, which protein in turn cannot exit the endoplasmic reticulum (ER) and traffic to the plasma membrane, and then is rapidly degraded. As a result, the number of channels present in the membrane is far less than in cells expressing wild-type CFTR. In addition to impaired trafficking, the mutation results in defective channel gating. Indeed, even if ΔF508-CFTR is allowed to reach the cell plasma membrane by low-temperature (27° C.) rescue where it can function as a cAMP-activated chloride channel, its activity is decreased significantly compared with WT-CFTR (Pasyk, E. A., Foskett, J. K., 1995. Mutant (ΔF508) Cystic Fibrosis Transmembrane Conductance Regulator Cl− Channel Is Functional When Retained in Endoplasmic Reticulum of Mammalian Cells. J. Biol. Chem. 270, 12347-12350).
Other mutations with lower incidence have also been identified that alter the channel regulation or the channel conductance. In case of the channel regulation mutants, the mutated protein is properly trafficked and localized to the plasma membrane but either cannot be activated or cannot function as a chloride channel (e.g. missense mutations located within the nucleotide binding domains), examples of these mutations are G551D, G178R, and G1349D. Mutations affecting chloride conductance have a CFTR protein that is correctly trafficked to the cell membrane but that generates reduced chloride flow (e.g. missense mutations located within the membrane-spanning domain), examples of these mutations are R117H and R334W.
In addition to cystic fibrosis, CFTR activity modulation may be beneficial for other diseases not directly caused by mutations in CFTR, such as, for example, chronic obstructive pulmonary disease (COPD), dry eye disease, and Sjogren's syndrome.
COPD is characterized by a progressive and non-reversible airflow limitation, which is due to mucus hypersecretion, bronchiolitis, and emphysema. A potential treatment of mucus hypersecretion and impaired mucociliary clearance that is common in COPD could consist in using activators of mutant or wild-type CFTR. In particular, the anion secretion increase across CFTR may facilitate fluid transport into the airway surface liquid to hydrate the mucus and optimize periciliary fluid viscosity. The resulting enhanced mucociliary clearance would help in reducing the symptoms associated with COPD.
Dry eye disease is characterized by a decrease in tear production and abnormal tear film lipid, protein and mucin profiles. Many factors may cause dry eye disease, some of which include age, arthritis, LASIK eye surgery, chemical/thermal burns, medications, allergies, and diseases, such as cystic fibrosis and Sjogrens's syndrome. Increasing anion secretion via CFTR could enhance fluid transport from the corneal endothelial cells and secretory glands surrounding the eye, and eventually improve corneal hydration, thus helping to alleviate dry eye disease associated symptoms. Sjogrens's syndrome is an autoimmune disease where the immune system harms moisture-producing glands throughout the body, including the eye, mouth, skin, respiratory tissue, liver, vagina, and gut. The ensuing symptoms, include, dry eye, mouth, and vagina, as well as lung disease. Sjogrens's syndrome is also associated with rheumatoid arthritis, systemic lupus, systemic sclerosis, and polymyositis/dermatomyositis. The cause of the disease is believed to lie in defective protein trafficking, for which treatment options are limited. As a consequence, modulation of CFTR activity may help hydrate the various organs and help alleviate the associated symptoms.
In addition to CF, the defective protein trafficking induced by the ΔF508-CFTR has been shown to be the underlying basis for a wide range of other diseases, in particular diseases where the defective functioning of the endoplasmic reticulum (ER) may either prevent the CFTR protein to exit the cell, and/or the misfolded protein is degraded (Morello, J.-P., Bouvier, M., Petaja-Repo, U. E., Bichet, D. G., 2000. Pharmacological chaperones: a new twist on receptor folding. Trends Pharmacol. Sci. 21, 466-469. doi:10.1016/S0165-6147(00)01575-3; Shastry, B. S., 2003. Neurodegenerative disorders of protein aggregation. Neurochem. Int. 43, 1-7. doi:10.1016/S0197-0186(02)00196-1; Zhang, W., Fujii, N., Naren, A. P., 2012. Recent advances and new perspectives in targeting CFTR for therapy of cystic fibrosis and enterotoxin-induced secretory diarrheas. Future Med. Chem. 4, 329-345. doi: 10.4155/fmc. 12.1).
A number of genetic diseases are associated with a defective ER processing equivalent to the defect observed with CFTR in CF such as glycanosis CDG type 1, hereditary emphysema (α-1-antitrypsin (PiZ variant)), congenital hyperthyroidism, osteogenesis imperfecta (Type I, II, or IV procollagen), hereditary hypofibrinogenemia (fibrinogen), ACT deficiency (α-1-antichymotrypsin), diabetes insipidus (DI), neurophyseal DI (vasopvessin hormoneN2-receptor), neprogenic DI (aquaporin II), Charcot-Marie Tooth syndrome (peripheral myelin protein 22), Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease (APP and presenilins), Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, several polyglutamine neurological disorders such as Huntington's disease, spinocerebullar ataxia type I, spinal and bulbar muscular atrophy, dentatorubal pallidoluysian, and myotonic dystrophy, as well as spongiform encephalopathies, such as hereditary Creutzfeldt-Jakob disease (prion protein processing defect), Fabry disease (lysosomal α-galactosidase A), Straussler-Scheinker syndrome, chronic obstructive pulmonary disease (COPD), dry eye disease, and Sjogren's Syndrome.
In addition to up-regulation of the activity of CFTR, anion secretion reduction by CFTR modulators may be beneficial for the treatment of secretory diarrheas, in which epithelial water transport is dramatically increased as a result of secretagogue activated chloride transport. The mechanism involves elevation of cAMP and stimulation of CFTR.
Regardless of the cause, excessive chloride transport is seen in all diarrhoeas, and results in dehydration, acidosis, impaired growth and death. Acute and chronic diarrhoeas remain a major medical problem worldwide, and are a significant factor in malnutrition, leading to death in children of less than five years old (5,000,000 deaths/year). Furthermore, in patients with chronic inflammatory bowel disease (IBD) and/or acquired immunodeficiency syndrome (AIDS), diarrhoea is a dangerous condition.
Accordingly, there is a need for novel compounds able to modulate CFTR. In particular, the present invention discloses compounds that may act as CFTR modulators for the treatment of cystic fibrosis. The present invention also provides methods for the preparation of these compounds, pharmaceutical compositions comprising these compounds and methods for the treatment of cystic fibrosis by administering the compounds of the invention.
SUMMARY
In one aspect the present invention provides for compounds of formula (I)




or a pharmaceutically acceptable salt thereof, wherein

    
    
        R1 is G1A, C1-C6 haloalkyl, or C1-C6 alkyl; wherein the C1-C6 haloalkyl and the C1-C6 alkyl are each optionally substituted with one G1A;
        G1A, at each occurrence, is independently phenyl, 5-6 membered monocyclic heteroaryl, 4-7 membered monocyclic heterocycle, 5-11 membered fused bicyclic heterocycle, or C3-C6 monocyclic cycloalkyl; wherein each G1A is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of R1a and G1B;
        G1B, at each occurrence, is independently 4-7 membered monocyclic heterocycle which is optionally substituted with 1, 2, 3, or 4 independently selected R1b groups;
        R2 is hydrogen, C2-C4 alkenyl, C1-C6 alkyl, C1-C6 haloalkyl, —OR2xa, —N(R2xa)(R2xb), or G2A;
        R2xa, at each occurrence, is independently C1-C6 alkyl, C1-C6 haloalkyl, or G2B;
        R2xb is hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl;
        G2A and G2B are each independently a 4-7 membered monocyclic heterocycle or a C3-C6 monocyclic cycloalkyl; wherein G2A and G2B are each optionally substituted with 1, 2, or 3 independently selected R2a groups;
        R3 is G3A, -G3B-L1-G3C, -G3B-L3-G3C-G3E, —(C1-C6 alkylenyl)-G3D, —OR3a, or —N(R3a)(R3b);
        R3a, at each occurrence, is independently G3D, C1-C6 haloalkyl, or C1-C6 alkyl; wherein the C1-C6 haloalkyl and the C1-C6 alkyl are each optionally substituted with one or two substituents independently selected from the group consisting of G3D, —OR3xa, and —N(R3xb)2;
        R3xa and R3xb, at each occurrence, are each independently hydrogen, C1-C6 haloalkyl, C1-C6 alkyl, or G3D;
        R3b is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl;
        L1 is a bond, C1-C6 alkylenyl, (C1-C6 alkylenyl)r-L2-(C1-C6 alkylenyl)s, or O—(C1-C6 alkylenyl)-C(O), wherein the left end of the L1 moiety is attached to G3B;
        L2 is O, N(Rx), C(O), N(Rx)C(O), or C(O)N(Rx); wherein each Rx is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl;
        L3 is a bond or C1-C6 alkylenyl;
        r is 0 or 1;
        s is 0 or 1;
        G3A, G3B, and G3C and each independently C3-C11 cycloalkyl, phenyl, 5-6 membered monocyclic heteroaryl, or 4-11 membered heterocycle; wherein G3A, G3B, and G3C are each optionally substituted with 1, 2, 3, or 4 independently selected Re groups;
        G3D, at each occurrence, is independently C3-C8 monocyclic cycloalkyl, 4-7 membered monocyclic heterocycle, a 5-11 membered fused bicyclic heterocycle, or a 5-11 membered spiro heterocycle; wherein each G3D is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of Re and G3E;
        G3E, at each occurrence, is independently C3-C8 monocyclic cycloalkyl or 4-7 membered monocyclic heterocycle; wherein each G3E is optionally substituted with 1, 2, 3, or 4 independently selected Re groups;
        R4 is hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl;
        R5 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, —N(R5ax)(R5bx), —OR5dx, or G5A; wherein the C1-C6 alkyl and the C1-C6 haloalkyl are each optionally substituted with one or two substituents independently selected from the group consisting of G5A, —CN, —N3, —OR5ax, —S(O)2R5ax, —S(O)2N(R5ax)(R5bx), —N(R5ax)(R5bx), —N(R5bx)S(O)2R5cx, —N(R5bx)C(O)R5cx, —N(R5bx)C(O)N(R5ax)(R5bx), —N(R5bx)C(O)OR5cx, —C(O)R5ax, —C(O)OR5ax, —C(O)N(R5bx)S(O)2R5cx, and —C(O)N(R5ax)(R5bx);
        R5ax and R5bx, at each occurrence, are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, —OR5ex, —(C1-C6 alkylenyl)-OR5ex, G5A, or —(C1-C6 alkylenyl)-G5A;
        R5cx, at each occurrence, is independently C1-C6 alkyl, C1-C6 haloalkyl, G5A, or —(C1-C6 alkylenyl)-G5A;
        R5dx is C1-C6 alkyl, or C1-C6 haloalkyl;
        R5ex is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl;
        G5A, at each occurrence, is independently C3-C11 cycloalkyl, phenyl, 5-6 membered monocyclic heteroaryl, or 4-11 membered heterocycle; wherein each G5A is optionally substituted with 1, 2, 3, or 4 independently selected R5a groups;
        R5a, at each occurrence, is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, oxo, G5B, —CN, NO2, —ORb, —OC(O)Rc, —OC(O)N(Rd)2, —SRb, —S(O)2Rb, —S(O)2N(Rd)2, —C(O)Rb, —C(O)ORb, —C(O)N(Rd)2, —C(O)N(Rd)S(O)2Rc, —N(Rd)2, —N(Rd)C(O)Rc, —N(Rd)S(O)2Rc, —N(Rd)C(O)O(Rb), —N(Rd)C(O)N(Rd)2, —N(Rd)S(O)2N(Rd)2, —(C1-C6 alkylenyl)-CN, —(C1-C6 alkylenyl)-G5B, —(C1-C6 alkylenyl)-ORb, —(C1-C6 alkylenyl)-OC(O)Rc, —(C1-C6 alkylenyl)-OC(O)N(Rd)2, —(C1-C6 alkylenyl)-SRb, —(C1-C6 alkylenyl)-S(O)2Rb, —(C1-C6 alkylenyl)-S(O)2N(Rd)2, —(C1-C6 alkylenyl)-C(O)Rb, —(C1-C6 alkylenyl)-C(O)ORb, —(C1-C6 alkylenyl)-C(O)N(Rd)2, —(C1-C6 alkylenyl)-C(O)N(Rd)S(O)2Rc, —(C1-C6 alkylenyl)-N(Rd)2, —(C1-C6 alkylenyl)-N(Rd)C(O)Rc, —(C1-C6 alkylenyl)-N(Rd)S(O)2Rc, —(C1-C6 alkylenyl)-N(Rd)C(O)O(Rc), —(C1-C6 alkylenyl)-N(Rd)C(O)N(Rd)2, or —(C1-C6 alkylenyl)-N(Rd)S(O)2N(Rd)2;
        Rb and Rd, at each occurrence, are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, alkoxyalkyl, G5B, or —(C1-C6 alkylenyl)-G5B;
        Rc, at each occurrence, is independently C1-C6 alkyl, C1-C6 haloalkyl, alkoxyalkyl, G5B, or —(C1-C6 alkylenyl)-G5B 
        G5B, at each occurrence, is independently C3-C6 monocyclic cycloalkyl, phenyl, 5-6 membered monocyclic heteroaryl, or 4-7 membered monocyclic heterocycle; wherein each G5B is optionally substituted with 1, 2, 3, or 4 independently selected R5b groups;
        Re, at each occurrence, is independently C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl, C1-C6 haloalkyl, halogen, oxo, —CN, —N3, NO2, —ORf, —OC(O)Rg, —OC(O)NRfRh, —SRf, —S(O)2Rf, —S(O)2NRfRh, —C(O)Rf, —C(O)ORf, —C(O)NRfRh, —C(O)N(Rh)S(O)2Rf, —N(Rf)2, —N(Rh)C(O)Rh, —N(Rh)S(O)2Rg, —N(Rh)C(O)O(Rg), —N(Rh)C(O)NRfRh, or —N(Rh)S(O)2NRfRh; wherein the C1-C6 haloalkyl and the C1-C6 alkyl are each optionally substituted with 1 or 2 substituents independently selected from the group consisting of —CN, NO2, —ORf, —OC(O)Rg, —OC(O)NRfRh, —SRf, —S(O)2Rf, —S(O)2NRfRh, —C(O)Rf, —C(O)ORf, —C(O)NRfRh, —C(O)N(Rh)S(O)2Rf, —N(Rf)2, —N(Rh)C(O)Rg, —N(Rh)S(O)2Rg, —N(Rh)C(O)O(Rg), —N(Rh)C(O)NRfRh, and —N(Rh)S(O)2NRfRh;
        Rf, at each occurrence, is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, —(C1-C6 alkylenyl)-CN, —(C1-C6 alkylenyl)-ORm, —(C1-C6 alkylenyl)-OC(O)Rn, —(C1-C6 alkylenyl)-OC(O)N(Rm)2, —(C1-C6 alkylenyl)-SRm, —(C1-C6 alkylenyl)-S(O)2Rm, —(C1-C6 alkylenyl)-S(O)2N(Rm)2, —(C1-C6 alkylenyl)-C(O)Rm, —(C1-C6 alkylenyl)-C(O)ORm, —(C1-C6 alkylenyl)-C(O)N(Rm)2, —(C1-C6 alkylenyl)-C(O)N(Rm)S(O)2Rn, —(C1-C6 alkylenyl)-N(Rm)2, —(C1-C6 alkylenyl)-N(Rm)C(O)Rn, —(C1-C6 alkylenyl)-N(Rm)S(O)2Rn, —(C1-C6 alkylenyl)-N(Rm)C(O)O(Rn), —(C1-C6 alkylenyl)-N(Rm)C(O)N(Rm)2, or —(C1-C6 alkylenyl)-N(Rm)S(O)2N(Rm)2;
        Rg, at each occurrence, is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, —(C1-C6 alkylenyl)-CN, —(C1-C6 alkylenyl)-ORm, —(C1-C6 alkylenyl)-OC(O)Rn, —(C1-C6 alkylenyl)-OC(O)N(Rm)2, —(C1-C6 alkylenyl)-SRm, —(C1-C6 alkylenyl)-S(O)2Rm, —(C1-C6 alkylenyl)-S(O)2N(Rm)2, —(C1-C6 alkylenyl)-C(O)Rm, —(C1-C6 alkylenyl)-C(O)ORm, —(C1-C6 alkylenyl)-C(O)N(Rm)2, —(C1-C6 alkylenyl)-C(O)N(Rm)S(O)2Rn, —(C1-C6 alkylenyl)-N(Rm)2, —(C1-C6 alkylenyl)-N(Rm)C(O)Rn, —(C1-C6 alkylenyl)-N(Rm)S(O)2Rn, —(C1-C6 alkylenyl)-N(Rm)C(O)O(Rn), —(C1-C6 alkylenyl)-N(Rm)C(O)N(Rm)2, or —(C1-C6 alkylenyl)-N(Rm)S(O)2N(Rm)2;
        Rh, at each occurrence, is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or —(C1-C6 alkylenyl)-ORm;
        R1a, R1b, R2a, and R5b, at each occurrence, are each independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, oxo, —CN, —NO2, —ORm, —OC(O)Rn, —OC(O)N(Rm)2, —SRm, —S(O)2Rm, —S(O)2N(Rm)2, —C(O)Rm, —C(O)ORm, —C(O)O(benzyl), —C(O)N(Rm)2, —C(O)N(Rm)S(O)2Rn, —N(Rm)2, —N(Rm)(alkoxyalkyl), —N(alkoxyalkyl)2, —N(Rm)C(O)Rn, —N(Rm)S(O)2Rn, —N(Rm)C(O)O(Rn), —N(Rm)C(O)N(Rm)2, —N(Rm)S(O)2N(Rm)2, —(C1-C6 alkylenyl)-CN, —(C1-C6 alkylenyl)-ORm, —(C1-C6 alkylenyl)-OC(O)Rn, —(C1-C6 alkylenyl)-OC(O)N(Rm)2, —(C1-C6 alkylenyl)-SRm, —(C1-C6 alkylenyl)-S(O)2Rm, —(C1-C6 alkylenyl)-S(O)2N(Rm)2, —(C1-C6 alkylenyl)-C(O)Rm, —(C1-C6 alkylenyl)-C(O)ORm, —(C1-C6 alkylenyl)-C(O)N(Rm)2, —(C1-C6 alkylenyl)-C(O)N(Rm)S(O)2Rn, —(C1-C6 alkylenyl)-N(Rm)2, —(C1-C6 alkylenyl)-N(Rm)C(O)Rn, —(C1-C6 alkylenyl)-N(Rm)S(O)2Rn, —(C1-C6 alkylenyl)-N(Rm)C(O)O(Rn), —(C1-C6 alkylenyl)-N(Rm)C(O)N(Rn)2, or —(C1-C6 alkylenyl)-N(Rm)S(O)2N(Rn)2;
        Rm, at each occurrence, is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl;
        Rn, at each occurrence, is independently C1-C6 alkyl or C1-C6 haloalkyl;
        R6 is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; or
        R5 and R6 together form a C1-C6 alkylenyl or —N(Rz)—(C1-C6 alkylenyl)- wherein the N(Rz) is attached to the S(O)2 moiety of formula (I); and
        Rz is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl.
    
    


Another aspect of the invention relates to pharmaceutical compositions comprising a compound of the invention, and a pharmaceutical carrier. Such compositions can be administered in accordance with a method of the invention, typically as part of a therapeutic regimen for treatment or prevention of conditions and disorders related to Cystic Fibrosis Transmembrane Conductance Regulator activity. In a particular aspect, the pharmaceutical compositions may additionally comprise further therapeutically active ingredients suitable for use in combination with the compounds of the invention. In a more particular aspect, the further therapeutically active ingredient is an agent for the treatment of cystic fibrosis.
Moreover, the compounds of the invention, useful in the pharmaceutical compositions and treatment methods disclosed herein, are pharmaceutically acceptable as prepared and used.
Yet another aspect of the invention relates to a method for treating, or preventing conditions and disorders related to Cystic Fibrosis Transmembrane Conductance Regulator activity in mammals. More particularly, the method is useful for treating or preventing conditions and disorders related to cystic fibrosis, Sjögren's syndrome, pancreatic insufficiency, chronic obstructive lung disease, or chronic obstructive airway disease. Accordingly, the compounds and compositions of the invention are useful as a medicament for treating or preventing Cystic Fibrosis Transmembrane Conductance Regulator modulated disease.
The compounds, compositions comprising the compounds, methods for making the compounds, and methods for treating or preventing conditions and disorders by administering the compounds are further described herein.
In a particular aspect, the compounds of the invention are provided for use in the treatment of cystic fibrosis. In a particular aspect, the compounds of the invention are provided for use in the treatment of cystic fibrosis caused by class I, II, III, IV, V, and/or VI mutations.
The present invention also provides pharmaceutical compositions comprising a compound of the invention, and a suitable pharmaceutical carrier for use in medicine. In a particular aspect, the pharmaceutical composition is for use in the treatment of cystic fibrosis.
These and other objects of the invention are described in the following paragraphs. These objects should not be deemed to narrow the scope of the invention.


DETAILED DESCRIPTION OF THE INVENTION
Described herein are compounds of formula (I)




wherein R1, R2, R3, R4, R5, and R6, are defined above in the Summary of the Invention and below in the Detailed Description. Further, compositions comprising such compounds and methods for treating conditions and disorders using such compounds and compositions are also described.

Compounds included herein may contain one or more variable(s) that occur more than one time in any substituent or in the formulae herein. Definition of a variable on each occurrence is independent of its definition at another occurrence. Further, combinations of substituents are permissible only if such combinations result in stable compounds. Stable compounds are compounds, which can be isolated from a reaction mixture.
Definitions
It is noted that, as used in this specification and the intended claims, the singular form “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a compound” includes a single compound as well as one or more of the same or different compounds; reference to “a pharmaceutically acceptable carrier” means a single pharmaceutically acceptable carrier as well as one or more pharmaceutically acceptable carriers, and the like.
As used in the specification and the appended claims, unless specified to the contrary, the following terms have the meaning indicated:
The term “alkenyl” as used herein, means a straight or branched hydrocarbon chain containing from 2 to 10 carbons and containing at least one carbon-carbon double bond. The term “C2-C6 alkenyl” means an alkenyl group containing 2-6 carbon atoms. Non-limiting examples of C2-C6 alkenyl include buta-1,3-dienyl, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, and 5-hexenyl.
The term “alkoxy” as used herein, means a C1-C6 alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Non-limiting examples of alkoxy include methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.
The term “alkoxyalkyl” as used herein, means an alkoxy group, as defined herein, appended to the parent molecular moiety through a C1-C6 alkyl group, as defined herein. Non-limiting examples of alkoxyalkyl include tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl, and methoxymethyl.
The term “alkyl” as used herein, means a saturated, straight or branched hydrocarbon chain radical. In some instances, the number of carbon atoms in an alkyl moiety is indicated by the prefix “Cx-Cy”, wherein x is the minimum and y is the maximum number of carbon atoms in the substituent. Thus, for example, “C1-C6 alkyl” means an alkyl substituent containing from 1 to 6 carbon atoms and “C1-C3 alkyl” means an alkyl substituent containing from 1 to 3 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-methylpropyl, 2-methylpropyl, 1-ethylpropyl, and 1,2,2-trimethylpropyl. The terms “alkyl,” “C1-C6 alkyl,” “C1-C4 alkyl,” and “C1-C3 alkyl” used herein are unsubstituted, unless otherwise indicated.
The term “alkylene” or “alkylenyl” means a divalent radical derived from a straight or branched, saturated hydrocarbon chain, for example, of 1 to 10 carbon atoms or of 1 to 6 carbon atoms (C1-C6 alkylenyl) or of 1 to 4 carbon atoms or of 1 to 3 carbon atoms (C1-C3 alkylenyl) or of 2 to 6 carbon atoms (C2-C6 alkylenyl). Examples of C1-C6 alkylenyl include, but are not limited to, —CH2—, —CH2CH2—, —C(CH3)2—CH2CH2CH2—, —C(CH3)2—CH2CH2—, —CH2CH2CH2CH2—, and —CH2CH(CH3)CH2—.
The term “C2-C6 alkynyl” as used herein, means a straight or branched chain hydrocarbon radical containing from 2 to 6 carbon atoms and containing at least one carbon-carbon triple bond. Representative examples of C2-C6 alkynyl include, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.
The term “C3-C11 cycloalkyl” as used herein, means a hydrocarbon ring radical containing 3-11 carbon atoms, zero heteroatom, and zero double bond. The C3-C11 cycloalkyl group may be a single-ring (monocyclic) or have two or more rings (polycyclic or bicyclic). Monocyclic cycloalkyl groups typically contain from 3 to 8 carbon ring atoms (C3-C8 monocyclic cycloalkyl), and even more typically 3-6 carbon ring atoms (C3-C6 monocyclic cycloalkyl). Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups contain two or more rings, and bicyclic cycloalkyls contain two rings. In certain embodiments, the polycyclic cycloalkyl groups contain 2 or 3 rings. The rings within the polycyclic and the bicyclic cycloalkyl groups may be in a bridged, fused, or spiro orientation, or combinations thereof. In a spirocyclic cycloalkyl, one atom is common to two different rings. An example of a spirocyclic cycloalkyl is spiro[4.5]decane. In a bridged cycloalkyl, the rings share at least two non-adjacent atoms. Examples of bridged cycloalkyls include, but are not limited to, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.1]nonyl, and bicyclo[4.2.1]nonyl, tricyclo[3.3.1.03,7]nonyl (octahydro-2,5-methanopentalenyl or noradamantyl), tricyclo[3.3.1.13,7]decyl (adamantyl), and tricyclo[4.3.1.13,8]undecyl (homoadamantyl). In a fused ring cycloalkyl, the rings share one common bond. Examples of fused-ring cycloalkyl include, but not limited to, decalin (decahydronaphthyl) and bicyclo[2.2.0]octyl.
The term “C4-C7 monocyclic cycloalkenyl” as used herein, means cyclobutenyl, cyclopentenyl, cyclohexenyl, and cycloheptyl.
The term “halo” or “halogen” as used herein, means Cl, Br, I, and F.
The term “haloalkyl” as used herein, means an alkyl group, as defined herein, in which one, two, three, four, five or six hydrogen atoms are replaced by halogen. The term “C1-C6 haloalkyl” means a C1-C6 alkyl group, as defined herein, in which one, two, three, four, five, or six hydrogen atoms are replaced by halogen. The term “C1-C3 haloalkyl” means a C1-C3 alkyl group, as defined herein, in which one, two, three, four, or five hydrogen atoms are replaced by halogen. Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, 2,2-difluoroethyl, fluoromethyl, 2,2,2-trifluoroethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl, 2-chloro-3-fluoropentyl, trifluorobutyl, and trifluoropropyl. The terms “haloalkyl,” “C1-C6 haloalkyl,” and “C1-C3 haloalkyl” used herein are unsubstituted, unless otherwise indicated.
The term “4-11 membered heterocycle” as used herein, means a hydrocarbon ring radical of 4-11 carbon ring atoms wherein at least one carbon atom is replaced by a heteroatom(s) independently selected from the group consisting of O, N, and S. The 4-11 membered heterocycle ring may be a single ring (monocyclic) or have two or more rings (bicyclic or polycyclic). In certain embodiments, the monocyclic heterocycle is a four-, five-, six-, seven-, or eight-membered hydrocarbon ring wherein at least one carbon ring atom is replaced by a heteroatom(s) independently selected from the group consisting of O, N, and S. In certain embodiments, the monocyclic heterocycle is a 4-7 membered hydrocarbon ring wherein at least one carbon ring atom is replaced by a heteroatom(s). A four-membered monocyclic heterocycle contains zero or one double bond, and one heteroatom selected from the group consisting of O, N, and S. A five-membered monocyclic heterocycle contains zero or one double bond and one, two, or three heteroatoms selected from the group consisting of O, N, and S. Examples of five-membered monocyclic heterocycles include those containing in the ring: 1 O; 1 S; 1 N; 2 N; 3N; 1 Sand 1 N; 1 S, and 2 N; 1 O and 1 N; or 1 O and 2 N. Non-limiting examples of 5-membered monocyclic heterocyclic groups include 1,3-dioxolanyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, imidazolidinyl, oxazolidinyl, imidazolinyl, imidazolidinyl, isoxazolidinyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, thiazolinyl, and thiazolidinyl. A six-membered monocyclic heterocycle contains zero, one, or two double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. Examples of six-membered monocyclic heterocycles include those containing in the ring: 1 O; 2 O; 1 S; 2 S; 1 N; 2 N; 3 N; 1 S, 1 O, and 1 N; 1 S and 1 N; 1 S and 2 N; 1 S and 1 O; 1 S and 2 O; 1 O and 1 N; and 1 O and 2 N. Examples of six-membered monocyclic heterocycles include 1,6-dihydropyridazinyl, dihydropyranyl, 1,3-dioxanyl, 1,4-dithianyl, hexahydropyrimidine, morpholinyl, piperazinyl, piperidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, tetrahydrothiopyranyl, thiomorpholinyl, thioxanyl, and trithianyl. Seven- and eight-membered monocyclic heterocycles contains zero, one, two, or three double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. Examples of monocyclic heterocycles include, but are not limited to, azetidinyl, azepanyl, aziridinyl, 1,4-diazepanyl, dihydropyranyl, 1,6-dihydropyridazinyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxazepanyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxetanyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyridinyl, tetrahydropyranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, thiopyranyl, and trithianyl. Polycyclic heterocycle groups contain two or more rings, and bicyclic heterocycles contain two rings. In certain embodiments, the polycyclic heterocycle groups contain 2 or 3 rings. The rings within the polycyclic and the bicyclic heterocycle groups may be in a bridged, fused, or spiro orientation, or combinations thereof. In a spirocyclic heterocycle, one atom is common to two different rings. Non-limiting examples of the spirocyclic heterocycle include 2-azaspiro[3.3]heptyl, 5-azaspiro[2.4]heptyl, 5-azaspiro[2.5]octyl, 2-azaspiro[3.5]nonyl, 2-azaspiro[3.4]octyl, 3-azaspiro[5.5]undecyl, 5-azaspiro[3.4]octyl, 2-oxaspiro[3.3]heptyl, 2-oxa-6-azaspiro[3.3]heptyl, 6-oxa-2-azaspiro[3.4]octyl, 6-azaspiro[3.4]octyl, 7-azaspiro[3.5]nonyl, 8-azaspiro[4.5]decyl, 1-oxa-7-azaspiro[4.4]nonyl, 1-oxa-7-azaspiro[3.5]nonyl, 1-oxa-8-azaspiro[4.5]decyl, 1-oxa-3,8-diazaspiro[4.5]decyl, 1-oxa-4,9-diazaspiro[5.5]undecyl, 3,9-diazaspiro[5.5]undecyl, 2-oxa-7-azaspiro[3.5]nonyl, 5-oxa-2-azaspiro[3.5]nonyl, 6-oxa-2-azaspiro[3.5]nonyl, 2-oxa-5,8-diazaspiro[3.5]nonyl, 7-oxa-2-azaspiro[3.5]nonyl, 8-oxa-1-azaspiro[4.5]decyl, 8-oxa-2-azaspiro[4.5]decyl, 2,7-diazaspiro[4.4]nonyl, 1,4-dioxa-8-azaspiro[4.5]decyl, 1,3,8-triazaspiro[4.5]decyl. In a fused ring heterocycle, the rings share one common bond. Examples of fused bicyclic heterocycles are a 4-6 membered monocyclic heterocycle fused to a phenyl group, or a 4-6 membered monocyclic heterocycle fused to a C3-C6 monocyclic cycloalkyl, or a 4-6 membered monocyclic heterocycle fused to a C4-C7 monocyclic cycloalkenyl, or a 4-6 membered monocyclic heterocycle fused to a 4-7 membered monocyclic heterocycle. Examples of fused bicyclic heterocycles include, but are not limited to, 1,3-benzodioxolyl, 3-azabicyclo[3.1.0]hexyl, benzopyranyl, benzothiopyranyl, indolinyl, decahydropyrrolo[3,4-b]azepinyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydro-1H-indolyl, 3,4-dihydroisoquinolin-2(1H)-yl, 2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazin-2-yl, hexahydropyrano[3,4-b][1,4]oxazin-1 (5H)-yl, hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl, hexahydrocyclopenta[c]pyrrol-3a(1H)-yl, hexahydro-1H-oxazolo[3,4-a]pyrazinyl, octahydropyrrolo[3,4-b][1,4]oxazinyl, octahydroimidazo[1,5-a]pyrazinyl, octahydropyrrolo[1,2-a]pyrazinyl, octahydro-1H-pyrrolo[3,2-c]pyridinyl, and octahydropyrrolo[3,4-c]pyrrolyl. In a bridged heterocycle, the rings share at least two non-adjacent atoms. Examples of such bridged heterocycles include, but are not limited to, azabicyclo[2.2.1]heptyl (including 2-azabicyclo[2.2.1]hept-2-yl and 2-oxa-5-azabicyclo[2.2.1]heptyl), 8-azabicyclo[3.2.1]oct-8-yl, octahydro-2,5-epoxypentalene, 8-oxa-3-azabicyclo[3.2.1]octyl, hexahydro-1H-1,4-methanocyclopenta[c]furan, aza-admantane (1-azatricyclo[3.3.1.13′7]decane), and oxa-adamantane (2-oxatricyclo[3.3.1.13′7]decane). The nitrogen and sulfur heteroatoms in the heterocycle rings may optionally be oxidized (e.g. 1,1-dioxidotetrahydrothienyl, 1,1-dioxido-1,2-thiazolidinyl, 1,1-dioxidothiomorpholinyl) and the nitrogen atoms may optionally be quaternized.
The term “5-11 membered heteroaryl” as used herein, means a monocyclic heteroaryl and a bicyclic heteroaryl. The monocyclic heteroaryl is a five- or six-membered ring. The five-membered ring contains two double bonds. The five membered ring may contain one heteroatom selected from O or S; or one, two, three, or four nitrogen atoms and optionally one oxygen or one sulfur atom. The six-membered ring contains three double bonds and one, two, three or four nitrogen atoms. Examples of 5-6 membered monocyclic heteroaryl include, but are not limited to, furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, 1,3-oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, 1,3-thiazolyl, thienyl, triazolyl, and triazinyl. The bicyclic heteroaryl consists of a monocyclic heteroaryl fused to a phenyl, or a monocyclic heteroaryl fused to a C3-C6 monocyclic cycloalkyl, or a monocyclic heteroaryl fused to C4-C7 monocyclic cycloalkenyl, or a monocyclic heteroaryl fused to a monocyclic heteroaryl, or a monocyclic heteroaryl fused to a 4-7 membered monocyclic heterocycle. Representative examples of bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzoxadiazolyl, phthalazinyl, 2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl, 6,7-dihydro-pyrazolo[1,5-a]pyrazin-5(4H)-yl, 6,7-dihydro-1,3-benzothiazolyl, imidazo[1,2-a]pyridinyl, indazolyl, indolyl, isoindolyl, isoquinolinyl, naphthyridinyl, pyridoimidazolyl, quinolinyl, 2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl, thiazolo[5,4-b]pyridin-2-yl, thiazolo[5,4-d]pyrimidin-2-yl, and 5,6,7,8-tetrahydroquinolin-5-yl. The nitrogen atom in the heteroaryl rings may optionally be oxidized and may optionally be quaternized.
The phenyl, the cycloalkyls, the cycloalkenyls, the heterocycles, and the heteroaryls, including the exemplary rings, are optionally substituted unless otherwise indicated; and are attached to the parent molecular moiety through any substitutable atom contained within the ring system.
The term “heteroatom” as used herein, means a nitrogen, oxygen, and sulfur.
The term “oxo” as used herein, means a ═O group.
The term “radiolabel” means a compound of the invention in which at least one of the atoms is a radioactive atom or a radioactive isotope, wherein the radioactive atom or isotope spontaneously emits gamma rays or energetic particles, for example alpha particles or beta particles, or positrons. Examples of such radioactive atoms include, but are not limited to, 3H (tritium), 14C, 11C, 15O, 18F, 35S, 123I, and 125I.
A moiety is described as “substituted” when a non-hydrogen radical is in the place of hydrogen radical of any substitutable atom of the moiety. Thus, for example, a substituted heterocycle moiety is a heterocycle moiety in which at least one non-hydrogen radical is in the place of a hydrogen radical on the heterocycle. It should be recognized that if there are more than one substitution on a moiety, each non-hydrogen radical may be identical or different (unless otherwise stated).
If a moiety is described as being “optionally substituted,” the moiety may be either (1) not substituted or (2) substituted. If a moiety is described as being optionally substituted with up to a particular number of non-hydrogen radicals, then that moiety may be either (1) not substituted; or (2) substituted by up to that particular number of non-hydrogen radicals or by up to the maximum number of substitutable positions on the moiety, whichever is less. Thus, for example, if a moiety is described as a heteroaryl optionally substituted with up to 3 non-hydrogen radicals, then any heteroaryl with less than 3 substitutable positions would be optionally substituted by up to only as many non-hydrogen radicals as the heteroaryl has substitutable positions. To illustrate, tetrazolyl (which has only one substitutable position) would be optionally substituted with up to one non-hydrogen radical. To illustrate further, if an amino nitrogen is described as being optionally substituted with up to 2 non-hydrogen radicals, then a primary amino nitrogen will be optionally substituted with up to 2 non-hydrogen radicals, whereas a secondary amino nitrogen will be optionally substituted with up to only 1 non-hydrogen radical.
The terms “treat”, “treating”, and “treatment” refer to a method of alleviating or abrogating a disease and/or its attendant symptoms. In certain embodiments, “treat,” “treating,” and “treatment” refer to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, “treat”, “treating”, and “treatment” refer to modulating the disease or disorder, either physically (for example, stabilization of a discernible symptom), physiologically (for example, stabilization of a physical parameter), or both. In a further embodiment, “treat”, “treating”, and “treatment” refer to slowing the progression of the disease or disorder.
The terms “prevent”, “preventing”, and “prevention” refer to a method of preventing the onset of a disease and/or its attendant symptoms or barring a subject from acquiring a disease. As used herein, “prevent”, “preventing” and “prevention” also include delaying the onset of a disease and/or its attendant symptoms and reducing a subject's risk of acquiring or developing a disease or disorder.
The phrase “therapeutically effective amount” means an amount of a compound, or a pharmaceutically acceptable salt thereof, sufficient to prevent the development of or to alleviate to some extent one or more of the symptoms of the condition or disorder being treated when administered alone or in conjunction with another therapeutic agent for treatment in a particular subject or subject population. The “therapeutically effective amount” may vary depending on the compound, the disease and its severity, and the age, weight, health, etc., of the subject to be treated. For example in a human or other mammal, a therapeutically effective amount may be determined experimentally in a laboratory or clinical setting, or may be the amount required by the guidelines of the United States Food and Drug Administration, or equivalent foreign agency, for the particular disease and subject being treated.
The term “subject” is defined herein to refer to animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, pigs, horses, dogs, cats, rabbits, rats, mice and the like. In one embodiment, the subject is a human. The terms “human,” “patient,” and “subject” are used interchangeably herein.
The term ‘one or more’ refers to one to four. In one embodiment it refers to one or three. In another embodiment it refers to one to three. In a further embodiment it refers to one to two. In yet other embodiment it refers to two. In yet other further embodiment it refers to one.
As used herein, “Class I mutation(s)” refers to mutations which interfere with protein synthesis. They result in the introduction of a premature signal of termination of translation (stop codon) in the mRNA. The truncated CFTR proteins are unstable and rapidly degraded, so, the net effect is that there is no protein at the apical membrane. In particular, Class I mutation(s) refers to p.Gly542X (G542X), W1282X, c.489+1G>T (621+1G>T), or c.579+1G>T (711+1G>T) mutation. More particularly, Class I mutation(s) refers to G542X; or W1282X mutations.
As used herein, “Class II mutation(s)” refers to mutations which affect protein maturation. These lead to the production of a CFTR protein that cannot be correctly folded and/or trafficked to its site of function on the apical membrane. In particular, Class II mutation(s) refers to p.Phe508del (F508del), p.Ile507del, or p.Asn1303Lys (N1303K) mutations. More particularly, Class II mutation(s) refers to F508del or N1303K mutations.
As used herein, “Class III mutation(s)” refers to mutations which alter the regulation of the CFTR channel. The mutated CFTR protein is properly trafficked and localized to the plasma membrane but cannot be activated, or it cannot function as a chloride channel. In particular, Class III mutation(s) refers to p.Gly551Asp (G551D), G551S, R553G, G1349D, S1251N, G178R, S549N mutations. More particularly, Class III mutation(s) refers to G551D, R553G, G1349D, S1251N, G178R, or S549N mutations.
As used herein, “Class IV mutation(s)” refers to mutations which affect chloride conductance. The CFTR protein is correctly trafficked to the cell membrane but generates reduced chloride flow or a “gating defect” (most are missense mutations located within the membrane-spanning domain). In particular, Class IV mutation(s) refers to p.Arg117His (R117H), R347P, or p.Arg334Trp (R334W) mutations.
As used herein, “Class V mutation(s)” refers to mutations which reduce the level of normally functioning CFTR at the apical membrane or result in a “conductance defect” (for example partially aberrant splicing mutations or inefficient trafficking missense mutations). In particular, Class V mutation(s) refers to c.1210-12T[5] (5T allele), c.S3140-26A>G (3272-26A>G), c.3850-2477C>T (3849+10kbC>T) mutations.
As used herein, “Class VI mutation(s)” refers to mutations which decrease the stability of the CFTR which is present or which affect the regulation of other channels, resulting in inherent instability of the CFTR protein. In effect, although functional, the CFTR protein is unstable at the cell surface and it is rapidly removed and degraded by cell machinery. In particular, Class VI mutation(s) refers to Rescued F508del, 120del23, N287Y, 4326del1TC, or 4279insA mutations. More particularly, Class VI mutation(s) refers to Rescued F508del mutations.
Compounds
Compounds of the invention have the general formula (I) as described above.
Particular values of variable groups in compounds of formula (I) are as follows. Such values may be used where appropriate with any of the other values, definitions, claims or embodiments defined hereinbefore or hereinafter.
In certain embodiments of formula (I), R1 is G1A, C1-C6 haloalkyl, or C1-C6 alkyl.
In certain embodiments of formula (I), R1 is G1A.
In certain embodiments of formula (I), R1 is G1A wherein G1A is phenyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, dihydropyranyl, 1,6-dihydropyridazinyl, tetrahydropyranyl, tetrahydrothienyl, piperidinyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
In certain embodiments of formula (I), R1 is G1A wherein G1A is phenyl, pyridinyl, tetrahydrofuranyl, tetrahydropyranyl, cyclopropyl, cyclopentyl, or cyclohexyl.
In certain embodiments of formula (I), R1 is G1A wherein G1A is phenyl, pyridinyl, or cyclohexyl.
In certain embodiments of formula (I), R1 is G1A wherein G1A is 4-7 membered monocyclic heterocycle. In some such embodiments, the 4-7 membered monocyclic heterocycle is tetrahydrofuranyl or tetrahydropyranyl.
In certain embodiments of formula (I), R1 is G1A wherein G1A is C3-C6 monocyclic cycloalkyl. In some such embodiments, the C3-C6 monocyclic cycloalkyl is cyclohexyl. In some such embodiments, the C3-C6 monocyclic cycloalkyl is cyclopentyl. In some such embodiments, the C3-C6 monocyclic cycloalkyl is cyclopropyl.
In certain embodiments, R1 is G1A wherein G1A is 5-11 membered fused bicyclic heterocycle. In some such embodiments, the 5-11 membered fused bicyclic heterocycle is 1,3-benzodioxolyl.
In certain embodiments of formula (I), R1 is G1A wherein G1A is phenyl or 5-6 membered monocyclic heteroaryl. In some such embodiments, the 5-6 membered monocyclic heteroaryl is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl. In some such embodiments, the 5-6 membered monocyclic heteroaryl is pyridinyl or pyrimidinyl. In some such embodiments, the 5-6 membered monocyclic heteroaryl is pyridinyl.
In certain embodiments of formula (I), R1 is G1A wherein G1A is phenyl.
In certain embodiments of formula (I), R1 is G1A wherein G1A is 5-6 membered monocyclic heteroaryl. In some such embodiments, the 5-6 membered monocyclic heteroaryl is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl. In some such embodiments, the 5-6 membered monocyclic heteroaryl is pyridinyl or pyrimidinyl. In some such embodiments, the 5-6 membered monocyclic heteroaryl is pyridinyl.
In certain embodiments, G1A, including the exemplary rings, are optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of R1a and G1B.
In certain embodiments, G1A, including the exemplary rings, are optionally substituted with 1, 2, 3, or 4 independently selected R1a.
In certain embodiments, G1A, including the exemplary rings, are optionally substituted with 1, 2, or 3 independently selected R1a.
In certain embodiments, G1A, including the exemplary rings, are optionally substituted with 1 or 2 independently selected R1a.
In certain embodiments, G1A, including the exemplary rings, are unsubstituted.
In certain embodiments, G1A, including the exemplary rings, are substituted with one G1B, and said G1A, including the exemplary rings, are optionally further substituted with 1, 2, or 3 independently selected R1a. In some such embodiments, said G1A, including the exemplary rings, are optionally further substituted with 1 or 2 independently selected R1a. In some such embodiments, said G1A, including the exemplary rings, are optionally further substituted with one R1a. In some such embodiments, said G1A, including the exemplary rings, are not further substituted.
In certain embodiments of formula (I), each R1a is independently C1-C6 alkyl, halogen, C1-C6 haloalkyl, oxo, —CN, —ORm, —S(O)2Rm, —S(O)2N(Rm)2, —C(O)Rm, —C(O)ORm, —C(O)N(Rm)2, —N(Rm)2, —N(Rm)(alkoxyalkyl), —N(alkoxyalkyl)2, or —(C1-C6 alkylenyl-CN).
In certain embodiments of formula (I), each R1a is independently C1-C6 alkyl, halogen, C1-C6 haloalkyl, —CN, —ORm, —N(Rm)2, —N(Rm)(alkoxyalkyl), or —N(alkoxyalkyl)2.
In certain embodiments of formula (I), each R1a is independently C1-C3 alkyl, halogen, C1-C3 haloalkyl, —CN, —ORm, or —N(Rm)2.
In certain embodiments of formula (I), G1B is a 4-7 membered monocyclic heterocycle.
In certain embodiments of formula (I), G1B is azetidinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, or morpholinyl.
In certain embodiments, G1B, including the exemplary rings, are optionally substituted with 1, 2, 3, or 4 independently selected R1b groups.
In certain embodiments, G1B, including the exemplary rings, are optionally substituted with 1, 2, or 3 independently selected R1b groups.
In certain embodiments, G1B, including the exemplary rings, are optionally substituted with 1 or 2 independently selected R1b.
In certain embodiments, G1B, including the exemplary rings, are unsubstituted.
In certain embodiments of formula (I), each R1b is independently C1-C3 alkyl, halogen, C1-C3 haloalkyl, or —ORm.
In certain embodiments of formula (I), R1 is C1-C6 alkyl. In some such embodiments, R1 is —C(CH3)3, —C(H)(CH3)2, or —CH2—CH(CH3)2. In some such embodiments, R1 is —C(H)(CH3)2 or —CH2—CH(CH3)2. In some such embodiments, R1 is —C(H)(CH3)2.
In certain embodiments of formula (I), R1 is C1-C6 alkyl substituted with one G1A. In some such embodiments, G1A is optionally substituted C3-C6 monocyclic cycloalkyl. In some such embodiments, G1A is optionally substituted cyclobutyl. In some such embodiments, G1A is unsubstituted cyclobutyl.
In certain embodiments of formula (I), R2 is C1-C6 alkyl, C1-C6 haloalkyl, —OR2xa, —N(R2xa)(R2xb), or G2A.
In certain embodiments of formula (I), R2 is C1-C6 alkyl, C1-C6 haloalkyl, —OR2xa, or G2A.
In certain embodiments of formula (I), R2 is C1-C6 alkyl, C1-C6 haloalkyl, or G2A.
In certain embodiments of formula (I), R2 is C1-C6 alkyl or G2A.
In certain embodiments of formula (I), R2 is —CH3, —C(H)(CH3)2, —C(CH3)3, or G2A.
In certain embodiments of formula (I), R2 is —CH3, —C(H)(CH3)2, or G2A.
In certain embodiments of formula (I), R2 is —C(H)(CH3)2 or G2A.
In certain embodiments of formula (I), R2 is C1-C6 alkyl.
In certain embodiments of formula (I), R2 is —CH3, —C(H)(CH3)2, or —C(CH3)3.
In certain embodiments of formula (I), R2 is —CH3 or —C(H)(CH3)2.
In certain embodiments of formula (I), R2 is G2A.
In certain embodiments, G2A is a C3-C6 monocyclic cycloalkyl. In some such embodiments, G2A is cyclopropyl or cyclobutyl. In some such embodiments, G2A is cyclobutyl.
In certain embodiments, G2A is a 4-7 membered monocyclic heterocycle. In some such embodiments, G2A is azetidinyl, oxetanyl, pyrrolidinyl, or tetrahydrofuranyl. In some such embodiments, G2A is azetidinyl or oxetanyl. In some such embodiments, G2A is azetidinyl.
In certain embodiments, G2A is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, cyclopropyl, or cyclobutyl.
In certain embodiments, G2A is azetidinyl, pyrrolidinyl, cyclopropyl, or cyclobutyl.
In certain embodiments, G2A is azetidinyl or cyclobutyl.
In certain embodiments, G2A is azetidinyl.
In certain embodiments, G2A is cyclobutyl.
In certain embodiments of formula (I), G2A, including the exemplary rings, are optionally substituted with 1, 2, or 3 independently selected R2a groups.
In certain embodiments of formula (I), G2A, including the exemplary rings, are optionally substituted with 1 or 2 independently selected R2a groups.
In certain embodiments of formula (I), G2A, including the exemplary rings, are unsubstituted.
In certain embodiments of formula (I), R2 is —OR2xa.
In certain embodiments of formula (I), R2 is —OR2xa wherein R2xa is C1-C6 alkyl or G2B.
In certain embodiments, G2B is a 4-7 membered monocyclic heterocycle.
In certain embodiments, G2B is azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl.
In certain embodiments, G2B is piperidinyl, oxetanyl, or tetrahydrofuranyl.
In certain embodiments, G2B is oxetanyl.
In certain embodiments, G2B is a C3-C6 monocyclic cycloalkyl. In some such embodiments, the C3-C6 monocyclic cycloalkyl is cyclobutyl.
In certain embodiments of formula (I), G2B, including the exemplary rings, are optionally substituted with 1, 2, or 3 independently selected R2a groups.
In certain embodiments of formula (I), G2B, including the exemplary rings, are optionally substituted with 1 or 2 independently selected R2a groups.
In certain embodiments of formula (I), G2B, including the exemplary rings, are unsubstituted.
In certain embodiments of formula (I), each R2a is independently C1-C6 alkyl, halogen, C1-C6 haloalkyl, oxo, —CN, —ORm, —C(O)Rm, —C(O)ORm, or —(C1-C6 alkylenyl)-CN.
In certain embodiments of formula (I), each R2a is independently C1-C3 alkyl, halogen, C1-C3 haloalkyl, —ORm, or —C(O)ORm.
In certain embodiments of formula (I), R3 is G3A, -G3B-L1-G3C, -G3B-L3-G3C-G3E-(C1-C6 alkylenyl)-G3D, or —OR3a.
In certain embodiments of formula (I), R3 is G3A, -G3B-L1-G3C, or —OR3a.
In certain embodiments of formula (I), R3 is G3A or -G3B-L1-G3C.
In certain embodiments of formula (I), R3 is G3A.
In certain embodiments of formula (I), R3 is G3A wherein G3A is phenyl, 5-6 membered monocyclic heteroaryl, or 4-11 membered heterocycle.
In certain embodiments of formula (I), R3 is G3A wherein G3A is phenyl or 5-6 membered monocyclic heteroaryl.
In certain embodiments of formula (I), R3 is G3A wherein G3A is phenyl, pyrazolyl, pyrrolyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl.
In certain embodiments of formula (I), R3 is G3A wherein G3A is phenyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl.
In certain embodiments of formula (I), R3 is G3A wherein G3A is phenyl, pyridinyl, or pyrimidinyl.
In certain embodiments of formula (I), R3 is G3A wherein G3A is phenyl.
In certain embodiments of formula (I), R3 is G3A wherein G3A is pyridinyl.
In certain embodiments of formula (I), R3 is G3A wherein G3A is a 4-11 membered heterocycle.
In certain embodiments of formula (I), R3 is G3A wherein G3A is azetidinyl, pyrrolidinyl, piperidinyl, dihydropyranyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyridinyl, azepanyl, 1,4-oxazepanyl, 1,4-diazepanyl, 2-azaspiro[3.3]heptyl, 2-oxaspiro[3.3]heptyl, 5-azaspiro[2.4]heptyl, 2-azaspiro[3.4]octyl, 5-azaspiro[2.5]octyl, 5-azaspiro[3.4]octyl, 5-oxa-2-azaspiro[3.5]nonyl, 6-oxa-2-azaspiro[3.4]octyl, 6-oxa-2-azaspiro[3.5]nonyl, 7-oxa-2-azaspiro[3.5]nonyl, 1-oxa-7-azaspiro[3.5]nonyl, 1-oxa-7-azaspiro[4.4]nonyl, 2-oxa-7-azaspiro[3.5]nonyl, 7-azaspiro[3.5]nonyl, 2,7-diazaspiro[4.4]nonyl, 2-azaspiro[3.5]nonyl, 1,3,8-triazaspiro[4.5]decyl, 8-azaspiro[4.5]decyl, 8-oxa-2-azaspiro[4.5]decyl, 1-oxa-8-azaspiro[4.5]decyl, 1-oxa-3,8-diazaspiro[4.5]decyl, 1-oxa-4,9-diazaspiro[5.5]undecyl, 1,4-dioxa-8-azaspiro[4.5]decyl, 3-azaspiro[5.5]undecyl, 3-azabicyclo[3.1.0]hexyl, 8-azabicyclo[3.2.1]octyl, octahydropyrrolo[3,4-c]pyrrolyl, hexahydro-1H-oxazolo[3,4-a]pyrazinyl, octahydropyrrolo[1,2-a]pyrazinyl, octahydroimidazo[1,5-a]pyrazinyl, octahydro-1H-pyrrolo[3,2-c]pyridinyl, decahydropyrrolo[3,4-b]azepinyl, or isoindolinyl.
In certain embodiments of formula (I), R3 is G3A wherein G3A is azetidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 2-azaspiro[3.3]heptyl, 5-azaspiro[2.4]heptyl, 2-azaspiro[3.4]octyl, 5-azaspiro[2.5]octyl, 5-oxa-2-azaspiro[3.5]nonyl, 6-oxa-2-azaspiro[3.5]nonyl, 7-oxa-2-azaspiro[3.5]nonyl, 1-oxa-7-azaspiro[3.5]nonyl, 2-azaspiro[3.5]nonyl, 1,3,8-triazaspiro[4.5]decyl, 8-oxa-2-azaspiro[4.5]decyl, 1-oxa-8-azaspiro[4.5]decyl, 1-oxa-3,8-diazaspiro[4.5]decyl, 3-azaspiro[5.5]undecyl, 3-azabicyclo[3.1.0]hexyl, or octahydro-1H-pyrrolo[3,2-c]pyridinyl.
In certain embodiments of formula (I), R3 is G3A is a 4-7 membered monocyclic heterocycle.
In certain embodiments of formula (I), R3 is G3A wherein G3A is azetidinyl, pyrrolidinyl, piperidinyl, dihydropyranyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyridinyl, azepanyl, 1,4-oxazepanyl, or 1,4-diazepanyl.
In certain embodiments of formula (I), R3 is G3A wherein G3A is azetidinyl, piperidinyl, or piperazinyl.
In certain embodiments of formula (I), R3 is G3A wherein G3A is piperidinyl or piperazinyl.
In certain embodiments of formula (I), R3 is G3A wherein G3A is piperidinyl.
In certain embodiments, each of the aforementioned G3A, including the exemplary rings, are optionally substituted with 1, 2, 3, or 4 independently selected Re groups.
In certain embodiments, each of the aforementioned G3A, including the exemplary rings, are optionally substituted with 1, 2, or 3 independently selected Re groups.
In certain embodiments, each of the aforementioned G3A, including the exemplary rings, are optionally substituted with 1 or 2 independently selected Re groups.
In certain embodiments, G3A, including the exemplary rings, are unsubstituted.
In certain embodiments, each of the optional substituents of G3A is independently C1-C6 alkyl, C1-C6 haloalkyl, halogen, oxo, —CN, —N3, —ORf, —S(O)2Rf, —C(O)Rf, —C(O)ORf, —C(O)NRfRh, —N(Rh)2, —N(Rh)C(O)Rh, —N(Rh)S(O)2Rg, or —N(Rh)C(O)O(Rg); wherein the C1-C6 haloalkyl and the C1-C6 alkyl are each optionally substituted with 1 or 2 substituents independently selected from the group consisting of —CN, —ORf, —N(Rf)2, —C(O)N(Rf)2, and —N(Rh)C(O)O(Rg).
In certain embodiments, each of the optional substituents of G3A is independently C1-C6 alkyl, C1-C6 haloalkyl, halogen, oxo, —CN, —N3, —ORf, —S(O)2Rf, —C(O)ORf, —N(Rf)2, or —N(Rh)C(O)Rh; wherein the C1-C6 haloalkyl and the C1-C6 alkyl are each optionally substituted with 1 or 2 substituents independently selected from the group consisting of —CN, —ORf, and —N(Rh)2; and each Rf is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, —(C1-C6 alkylenyl)-ORm, or —(C1-C6 alkylenyl)-N(Rm)2.
In certain embodiments, each of the optional substituents of G3A is independently C1-C6 alkyl, C1-C6 haloalkyl, halogen, —ORf, or —N(Rf)2; wherein the C1-C6 haloalkyl and the C1-C6 alkyl are each optionally substituted with 1 or 2 substituents independently selected from the group consisting of —ORf and —N(Rf)2; and each Rf is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, —(C1-C6 alkylenyl)-ORm, or —(C1-C6 alkylenyl)-N(Rm)2.
In certain embodiments of formula (I), R3 is -G3B-L1-G3C.
In certain embodiments of formula (I), G3B is phenyl, 5-6 membered monocyclic heteroaryl, or 4-7 membered monocyclic heterocycle.
In certain embodiments of formula (I), G3B is phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, 1-oxa-8-azaspiro[4.5]decyl, 3,9-diazaspiro[5.5]undecyl, octahydro-1H-pyrrolo[3,2-c]pyridinyl, or 1,4-diazepanyl.
In certain embodiments of formula (I), G3B is phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, piperidinyl, or piperazinyl.
In certain embodiments of formula (I), G3B is phenyl, pyridinyl, pyrimidinyl, piperidinyl, or piperazinyl.
In certain embodiments of formula (I), G3B is a 4-7 membered monocyclic heterocycle.
In certain embodiments of formula (I), G3B is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or 1,4-diazepanyl.
In certain embodiments of formula (I), G3B is piperidinyl or piperazinyl.
In certain embodiments of formula (I), G3B is piperidinyl.
In certain embodiments of formula (I), G3B is piperazinyl.
In certain embodiments of formula (I), G3C is C3-C6 monocyclic cycloalkyl, phenyl, 5-6 membered monocyclic heteroaryl, or 4-7 membered monocyclic heterocycle.
In certain embodiments of formula (I), G3C is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, oxazolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, thiomorpholinyl, 2-oxa-5,8-diazaspiro[3.5]nonyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, hexahydropyrrolo[3,4-c]pyrrolyl, or morpholinyl.
In certain embodiments of formula (I), G3C is 4-7 membered monocyclic heterocycle.
In certain embodiments of formula (I), G3C is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, oxazolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, thiomorpholinyl, or morpholinyl.
In certain embodiments of formula (I), G3C is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydropyranyl, or morpholinyl.
In certain embodiments of formula (I), G3C is pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl.
In certain embodiments, each of the aforementioned G3B and G3C, including the exemplary rings, are optionally substituted with 1, 2, 3, or 4 independently selected Re groups.
In certain embodiments, each of the aforementioned G3B and G3C, including the exemplary rings, are optionally substituted with 1, 2, or 3 independently selected Re groups.
In certain embodiments, each of the aforementioned G3B and G3C, including the exemplary rings, are optionally substituted with 1 or 2 independently selected Re groups.
In certain embodiments, G3B and G3C, including the exemplary rings, are unsubstituted.
In certain embodiments, each of the optional substituents of G3B is independently C1-C6 alkyl, C1-C6 haloalkyl, halogen, —ORf, or —CN. In some such embodiments, Rf is hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl.
In certain embodiments, each of the optional substituents of G3B is independently —CH3, —CH2F, —CHF2, —CF3, or F.
In certain embodiments, each of the optional substituents of G3C is independently C1-C6 alkyl, C1-C6 haloalkyl, halogen, oxo, —ORf, —N(Rf)2, —C(O)ORf, or —CN; wherein the C1-C6 alkyl is optionally substituted with one —ORf.
In certain embodiments, each of the optional substituents of G3C is independently —CH3, —CH2F, —CHF2, —CF3, F, or —CN.
In certain embodiments, L1 is a bond, C1-C3 alkylenyl, or (C1-C3 alkylenyl)r-L2-(C1-C3 alkylenyl)s.
In certain embodiments, L2 is O, N(Rx), or C(O).
In certain embodiments, L2 is O or N(Rx).
In certain embodiments of formula (I), R3 is —OR3a.
In certain embodiments of formula (I), R3 is —OR3a wherein R3a is G3D, C1-C6 haloalkyl, or C1-C6 alkyl; wherein the C1-C6 haloalkyl and the C1-C6 alkyl are each substituted with one or two substituents independently selected from the group consisting of G3D, —OR3xa, and —N(R3xb)2.
In certain embodiments of formula (I), R3 is —OR3a; and R3a is C1-C6 haloalkyl and C1-C6 alkyl; wherein the C1-C6 haloalkyl and the C1-C6 alkyl are each substituted with one G3D.
In certain embodiments, G3D is oxetanyl, pyrrolidinyl, tetrahydrofuranyl, imidazolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, thiomorpholinyl, morpholinyl, 1,3-dioxolanyl, azepanyl, 1,4-diazepanyl, 1,3-dioxanyl, 1,4-dioxanyl, 8-azaspiro[4.5]decyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
In certain embodiments, G3D is a 4-7 membered monocyclic heterocycle.
In certain embodiments, G3D is oxetanyl, pyrrolidinyl, tetrahydrofuranyl, imidazolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, thiomorpholinyl, morpholinyl, 1,3-dioxolanyl, azepanyl, 1,4-diazepanyl, 1,3-dioxanyl, or 1,4-dioxanyl.
In certain embodiments, G3D is tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, thiomorpholinyl, morpholinyl, or 1,4-dioxanyl.
In certain embodiments, G3D is tetrahydropyranyl.
In certain embodiments, each of the aforementioned G3D, including the exemplary rings, are optionally substituted with 1, 2, 3, or 4 independently substituents independently selected from the group consisting of Re and G3E.
In certain embodiments, each of the aforementioned G3D, including the exemplary rings, are optionally substituted with 1, 2, or 3 independently selected Re groups.
In certain embodiments, each of the aforementioned G3D, including the exemplary rings, are optionally substituted with 1 or 2 independently selected Re groups.
In certain embodiments, each of the aforementioned G3D, including the exemplary rings, are optionally substituted with one G3E and optionally with 1 or 2 independently selected Re groups. Examples of G3E include cyclobutyl, cyclohexyl, and tetrahydropyranyl, each of which is optionally substituted.
In certain embodiments, G3D, including the exemplary rings, are unsubstituted. In certain embodiments, each of the Re groups of G3D is independently C1-C6 alkyl, C1-C6 haloalkyl, halogen, oxo, —ORf, —C(O)Rf, —C(O)ORf, or —CN.
In certain embodiments of formula (I), R3 is —N(R3a)(R3b).
In certain embodiments of formula (I), R3 is —N(R3a)(R3b) wherein R3a is C1-C3 haloalkyl or C1-C3 alkyl; wherein the C1-C3 haloalkyl and the C1-C3 alkyl are each substituted with one substituent independently selected from the group consisting of —OR3xa and —N(R3xb)2. In some such embodiments, R3xa and R3xb, at each occurrence, are each independently hydrogen, C1-C3 haloalkyl, or C1-C3 alkyl.
In certain embodiments of formula (I), R3 is -G3B-L3-G3-G3E. In some such embodiments, G3B is phenyl, 5-6 membered heteroaryl, or 4-11 membered heterocycle, G3C is 4-11 membered heterocycle; and G3E is C3-C8 monocyclic cycloalkyl. Examples of G3B are phenyl, pyridinyl, piperidinyl, and piperazinyl. In some such embodiments, G3C is piperidinyl or piperazinyl. In some such embodiments, G3E is cyclopropyl. G3B, G3C, and G3E, including the exemplary rings, are each optionally substituted as described in the summary and embodiments herein above.
In certain embodiments, R3 is —(C1-C6 alkylenyl)-G3D. In some such embodiments, G3D is 4-7 membered monocyclic heterocycle. In some such embodiments, G3D is piperidinyl, piperazinyl or morpholinyl. G3D, including the exemplary rings are each optionally substituted as described in the Summary and embodiments herein above.
In certain embodiments of formula (I), R4 is hydrogen or C1-C3 alkyl.
In certain embodiments of formula (I), R4 is hydrogen.
In certain embodiments of formula (I), R5 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl; wherein the C1-C6 alkyl and the C1-C6 haloalkyl are each optionally substituted with one or two substituents independently selected from the group consisting of G5A, —CN, —N3, —OR5ax, —S(O)2R5ax, —S(O)2N(R5ax)(R5bx), —N(R5ax)(R5bx), —N(R5bx)S(O)2R5cx, —N(R5bx)C(O)R5cx, —N(R5bx)C(O)N(R5ax)(R5bx), —N(R5bx)C(O)OR5cx, —C(O)R5ax, —C(O)OR5ax, —C(O)N(R5bx)S(O)2R5cx, and —C(O)N(R5ax)(R5bx).
In certain embodiments of formula (I), R5 is C1-C6 alkyl or C1-C6 haloalkyl.
In certain embodiments of formula (I), R5 is —CH3, —CH2CH3, —CH2C(H)C(CH3)2, —C(CH3)3, —CF3, —CH2Cl, —CH2CF3, or —CH2CH2CF3.
In certain embodiments of formula (I), R5 is —CH3.
In certain embodiments of formula (I), R5 is C1-C6 alkyl which is substituted with one substituent selected from the group consisting of G5A, —CN, —N3, —OR5ax, —S(O)2R5ax, —S(O)2N(R5ax)(R5bx), —N(R5ax)(R5bx), —N(R5bx)S(O)2R5cx, —N(R5bx)C(O)R5cx, —N(R5bx)C(O)N(R5ax)(R5bx), —N(R5bx)C(O)OR5cx, —C(O)R5ax, —C(O)OR5ax, —C(O)N(R5bx)S(O)2R5cx, and —C(O)N(R5ax)(R5bx).
In certain embodiments of formula (I), R5 is C1-C6 alkyl which is substituted with one substituent selected from the group consisting of G5A, —CN, —N3, —OR5ax, —N(R5ax)(R5bx), —N(R5bx)C(O)R5cx, —N(R5bx)C(O)OR5cx, —C(O)OR5ax, and —C(O)N(R5ax)(R5bx).
In certain embodiments of formula (I), R5 is C1-C6 alkyl substituted with one G5A. In some such embodiments, G5A is 5-6 membered monocyclic heteroaryl or a 4-11 membered heterocycle.
In certain embodiments of formula (I), R5 is —N(R5ax)(R5bx). In some such embodiments, R5ax is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; and R5bx is C1-C6 alkyl, C1-C6 haloalkyl or G5A. In some such embodiments, R5ax and R5bx are each C1-C6 alkyl.
In certain embodiments of formula (I), R5 is G5A.
In certain embodiments of formula (I), R5 is G5A wherein G5A is C3-C6 monocyclic cycloalkyl, phenyl, 5-6 membered monocyclic heteroaryl, or 4-11 membered heterocycle.
In certain embodiments, each of the aforementioned G5A is optionally substituted with 1, 2, 3, or 4 independently selected R5a groups.
In certain embodiments, G5A is optionally substituted with 1, 2, or 3, independently selected R5a groups.
In certain embodiments, G5A is optionally substituted with 1, or 2 independently selected R5a groups.
In certain embodiments, G5A is unsubstituted.
In certain embodiments of formula (I), R6 is hydrogen.
In certain embodiments of formula (I), R6 is C1-C6 alkyl or C1-C6 haloalkyl.
In certain embodiments of formula (I), R6 is C1-C6 alkyl. In some such embodiments, R6 is —CH3.
In certain embodiments of formula (I), R5 and R6 together form a C1-C6 alkylenyl or —N(Rz)—(C1-C6 alkylenyl)- wherein the N(Rz) is attached to the S(O)2 moiety of formula (I).
In certain embodiments of formula (I), R5 and R6 together form a C1-C6 alkylenyl.
In certain embodiments of formula (I), R5 and R6 together form a —N(Rz)—(C1-C6 alkylenyl)- wherein the N(Rz) is attached to the S(O)2 moiety of formula (I).
Various embodiments of substituents R1, R2, R3, R4, R5, R6, G1A, R1a, G1B, R1b, G2AG2B, R2a, R2xa, G3A, G3B, G3C, Re, Rf, L1, L2, R3a, G3D, G5A, R5ax, and R5bx have been discussed above. These substituents embodiments can be combined to form various embodiments of the invention. All embodiments of present compounds, formed by combining the substituent embodiments discussed above are within the scope of Applicant's invention, and some illustrative embodiments of present compounds are provided below.
In one embodiment, the invention is directed to compounds wherein R1 is G1A, C1-C6 haloalkyl, or C1-C6 alkyl; and R2 is C1-C6 alkyl, C1-C6 haloalkyl, or G2A. In some such embodiments, R6 is hydrogen. In some such embodiments, R6 is C1-C6 alkyl or C1-C6 haloalkyl. In some such embodiments, R6 is C1-C6 alkyl. In some such embodiments, R6 is —CH3. In some such embodiments, R5 and R6 together form a C1-C6 alkylenyl or —N(Rz)—(C1-C6 alkylenyl)- wherein the N(Rz) is attached to the S(O)2 moiety of formula (I).
In one embodiment, the invention is directed to compounds wherein R1 is G1A; and R2 is C1-C6 alkyl or G2A. In some such embodiments, R6 is hydrogen. In some such embodiments, R6 is C1-C6 alkyl or C1-C6 haloalkyl. In some such embodiments, R6 is C1-C6 alkyl. In some such embodiments, R6 is —CH3. In some such embodiments, R5 and R6 together form a C1-C6 alkylenyl or —N(Rz)—(C1-C6 alkylenyl)- wherein the N(Rz) is attached to the S(O)2 moiety of formula (I).
In one embodiment, the invention is directed to compounds wherein R1 is G1A wherein G1A is phenyl or 5-6 membered monocyclic heteroaryl; and R2 is C1-C6 alkyl or G2A wherein G2A is C3-C6 monocyclic cycloalkyl. In some such embodiments, R6 is hydrogen. In some such embodiments, R6 is C1-C6 alkyl or C1-C6 haloalkyl. In some such embodiments, R6 is C1-C6 alkyl. In some such embodiments, R6 is —CH3. In some such embodiments, R5 and R6 together form a C1-C6 alkylenyl or —N(Rz)—(C1-C6 alkylenyl)- wherein the N(Rz) is attached to the S(O)2 moiety of formula (I).
In one embodiment, the invention is directed to compounds wherein R1 is G1A wherein G1A is phenyl or pyridinyl; and R2 is C1-C6 alkyl. In some such embodiments, R6 is hydrogen. In some such embodiments, R6 is C1-C6 alkyl or C1-C6 haloalkyl. In some such embodiments, R6 is C1-C6 alkyl. In some such embodiments, R6 is —CH3. In some such embodiments, R5 and R6 together form a C1-C6 alkylenyl or —N(Rz)—(C1-C6 alkylenyl)- wherein the N(Rz) is attached to the S(O)2 moiety of formula (I).
In one embodiment, the invention is directed to compounds wherein R1 is G1A wherein G1A is phenyl or pyridinyl; and R2 is G2A wherein G2A is C3-C6 monocyclic cycloalkyl. In some such embodiments, R6 is hydrogen. In some such embodiments, R6 is C1-C6 alkyl or C1-C6 haloalkyl. In some such embodiments, R6 is C1-C6 alkyl. In some such embodiments, R6 is —CH3. In some such embodiments, R5 and R6 together form a C1-C6 alkylenyl or —N(Rz)—(C1-C6 alkylenyl)- wherein the N(Rz) is attached to the S(O)2 moiety of formula (I).
In one embodiment, the invention is directed to compounds wherein R1 is G1A wherein G1A is phenyl or pyridinyl; and R2 is G2A wherein G2A is unsubstituted cyclobutyl. In some such embodiments, R6 is hydrogen. In some such embodiments, R6 is C1-C6 alkyl or C1-C6 haloalkyl. In some such embodiments, R6 is C1-C6 alkyl. In some such embodiments, R6 is —CH3. In some such embodiments, R5 and R6 together form a C1-C6 alkylenyl or —N(Rz)—(C1-C6 alkylenyl)- wherein the N(Rz) is attached to the S(O)2 moiety of formula (I).
In one embodiment, the invention is directed to compounds wherein R1 is G1A; R2 is C1-C6 alkyl or G2A; and R3 is G3A, -G3B-L1-G3C, or —OR3a. In some such embodiments, R6 is hydrogen. In some such embodiments, R6 is C1-C6 alkyl or C1-C6 haloalkyl. In some such embodiments, R6 is C1-C6 alkyl. In some such embodiments, R6 is —CH3. In some such embodiments, R5 and R6 together form a C1-C6 alkylenyl or —N(Rz)—(C1-C6 alkylenyl)- wherein the N(Rz) is attached to the S(O)2 moiety of formula (I).
In one embodiment, the invention is directed to compounds wherein R1 is G1A; R2 is C1-C6 alkyl or G2A; and R5 is C1-C6 alkyl or C1-C6 haloalkyl. In some such embodiments, R6 is hydrogen. In some such embodiments, R6 is C1-C6 alkyl or C1-C6 haloalkyl. In some such embodiments, R6 is C1-C6 alkyl. In some such embodiments, R6 is —CH3.
In one embodiment, the invention is directed to compounds wherein R1 is G1A; R2 is C1-C6 alkyl or G2A; and R5 is C1-C6 alkyl which is substituted with one substituent selected from the group consisting of G5A, —CN, —N3, —OR5ax, —N(R5ax)(R5bx), —N(R5bx)C(O)R5cx, —N(R5bx)C(O)OR5cx, —C(O)OR5ax, and —C(O)N(R5ax)(R5bx). In some such embodiments, R6 is hydrogen. In some such embodiments, R6 is C1-C6 alkyl or C1-C6 haloalkyl. In some such embodiments, R6 is C1-C6 alkyl. In some such embodiments, R6 is —CH3.
In one embodiment, the invention is directed to compounds wherein R1 is G1A; R2 is C1-C6 alkyl or G2A; and R5 is —N(R5ax)(R5bx). In some such embodiments, R6 is hydrogen. In some such embodiments, R6 is C1-C6 alkyl or C1-C6 haloalkyl. In some such embodiments, R6 is C1-C6 alkyl. In some such embodiments, R6 is —CH3.
In one embodiment, the invention is directed to compounds wherein R1 is G1A; R2 is C1-C6 alkyl or G2A; and R5 is G5A. In some such embodiments, R6 is hydrogen. In some such embodiments, R6 is C1-C6 alkyl or C1-C6 haloalkyl. In some such embodiments, R6 is C1-C6 alkyl. In some such embodiments, R6 is —CH3.
In one embodiment, the invention is directed to compounds wherein R1 is G1A; wherein G1A is phenyl or 5-6 membered monocyclic heteroaryl; R2 is C1-C6 alkyl or G2A; wherein G2A is a C3-C6 monocyclic cycloalkyl; R3 is G3A, -G3B-L1-G3C, or —OR3a; and R5 is C1-C6 alkyl which is substituted with one substituent selected from the group consisting of G5A, —CN, —N3, —OR5ax, —N(R5ax)(R5bx), —N(R5bx)C(O)R5cx, —N(R5bx)C(O)OR5cx, —C(O)OR5ax, and —C(O)N(R5ax)(R5bx). In some such embodiments, R6 is hydrogen. In some such embodiments, R6 is C1-C6 alkyl or C1-C6 haloalkyl. In some such embodiments, R6 is C1-C6 alkyl. In some such embodiments, R6 is —CH3.
In one embodiment, the invention is directed to compounds wherein R1 is G1A; wherein G1A is phenyl or 5-6 membered monocyclic heteroaryl; R2 is C1-C6 alkyl or G2A; wherein G2A is a C3-C6 monocyclic cycloalkyl; R3 is G3A, -G3B-L1-G3C, or —OR3a; and R5 is C1-C6 alkyl or C1-C6 haloalkyl. In some such embodiments, R6 is hydrogen. In some such embodiments, R6 is C1-C6 alkyl or C1-C6 haloalkyl. In some such embodiments, R6 is C1-C6 alkyl. In some such embodiments, R6 is —CH3.
In one embodiment, the invention is directed to compounds wherein R1 is G1A; wherein G1A is phenyl or 5-6 membered monocyclic heteroaryl; R2 is C1-C6 alkyl or G2A; wherein G2A is a C3-C6 monocyclic cycloalkyl; R3 is G3A, -G3B-L1-G3C, or —OR3a; and R5 is —N(R5ax)(R5bx) or —OR5dx. In some such embodiments, R6 is hydrogen. In some such embodiments, R6 is C1-C6 alkyl or C1-C6 haloalkyl. In some such embodiments, R6 is C1-C6 alkyl. In some such embodiments, R6 is —CH3.
In one embodiment, the invention is directed to compounds wherein R1 is G1A; wherein G1A is phenyl or 5-6 membered monocyclic heteroaryl; R2 is C1-C6 alkyl or G2A; wherein G2A is a C3-C6 monocyclic cycloalkyl; R3 is G3A, -G3B-L1-G3C, or —OR3a; and R5 is G5A. In some such embodiments, R6 is hydrogen. In some such embodiments, R6 is C1-C6 alkyl or C1-C6 haloalkyl. In some such embodiments, R6 is C1-C6 alkyl. In some such embodiments, R6 is —CH3.
In one embodiment, the invention is directed to compounds wherein R1 is G1A; wherein G1A is phenyl optionally substituted with 1, 2, 3, or 4 independently selected R1a; R2 is C1-C6 alkyl or G2A; wherein G2A is unsubstituted cyclobutyl; R3 is G3A wherein G3A is a 4-11 membered heterocycle; and R5 is C1-C6 alkyl. In some such embodiments, R6 is hydrogen. In some such embodiments, R6 is C1-C6 alkyl or C1-C6 haloalkyl. In some such embodiments, R6 is C1-C6 alkyl. In some such embodiments, R6 is —CH3.
In one embodiment, the invention is directed to compounds wherein R1 is G1A; wherein G1A is phenyl substituted with one G1B, and said phenyl is optionally further substituted with 1, 2, or 3 independently selected R1a; R2 is C1-C6 alkyl or G2A; wherein G2A is unsubstituted cyclobutyl; R3 is G3A wherein G3A is a 4-11 membered heterocycle; and R5 is C1-C6 alkyl. In some such embodiments, R6 is hydrogen. In some such embodiments, R6 is C1-C6 alkyl or C1-C6 haloalkyl. In some such embodiments, R6 is C1-C6 alkyl. In some such embodiments, R6 is —CH3.
In one embodiment, the invention is directed to compounds wherein R1 is G1A; wherein G1A is phenyl optionally substituted with 1, 2, 3, or 4 independently selected R1a; R2 is C1-C6 alkyl or G2A; wherein G2A is unsubstituted cyclobutyl; R3 is -G3B-L1-G3C; and R5 is C1-C6 alkyl. In some such embodiments, R6 is hydrogen. In some such embodiments, R6 is C1-C6 alkyl or C1-C6 haloalkyl. In some such embodiments, R6 is C1-C6 alkyl. In some such embodiments, R6 is —CH3.
In one embodiment, the invention is directed to compounds wherein R1 is G1A; wherein G1A is phenyl optionally substituted with 1, 2, 3, or 4 independently selected R1a; R2 is C1-C6 alkyl or G2A; wherein G2A is unsubstituted cyclobutyl; R3 is -G3B-L1-G3C; G3B and G3C are 4-7 membered monocyclic heterocycle; and R5 is C1-C6 alkyl. In some such embodiments, R6 is hydrogen. In some such embodiments, R6 is C1-C6 alkyl or C1-C6 haloalkyl. In some such embodiments, R6 is C1-C6 alkyl. In some such embodiments, R6 is —CH3.
In one embodiment, the invention is directed to compounds wherein R1 is G1A; wherein G1A is phenyl substituted with one G1B, and said phenyl is optionally further substituted with 1, 2, or 3 independently selected R1a; R2 is C1-C6 alkyl or G2A; wherein G2A is unsubstituted cyclobutyl; R3 is -G3B-L1-G3C; G3B and G3C are 4-7 membered monocyclic heterocycle; and R5 is C1-C6 alkyl. In some such embodiments, R6 is hydrogen. In some such embodiments, R6 is C1-C6 alkyl or C1-C6 haloalkyl. In some such embodiments, R6 is C1-C6 alkyl. In some such embodiments, R6 is —CH3.
In one embodiment, the invention is directed to compounds wherein R1 is G1A; wherein G1A is phenyl optionally substituted with 1, 2, 3, or 4 independently selected R1a; R2 is C1-C6 alkyl or G2A; wherein G2A is unsubstituted cyclobutyl; R3 is —OR3a; R3a is C1-C6 alkyl or C1-C6 haloalkyl wherein the C1-C6 alkyl and the C1-C6 haloalkyl are each substituted with one G3D; G3D is a 4-7 membered monocyclic heterocycle; and R5 is C1-C6 alkyl. In some such embodiments, R6 is hydrogen. In some such embodiments, R6 is C1-C6 alkyl or C1-C6 haloalkyl. In some such embodiments, R6 is C1-C6 alkyl. In some such embodiments, R6 is —CH3.
In one embodiment, the invention is directed to compounds wherein R1 is G1A; wherein G1A is phenyl substituted with one G1B, and said phenyl is optionally further substituted with 1, 2, or 3 independently selected R1a; R2 is C1-C6 alkyl or G2A; wherein G2A is unsubstituted cyclobutyl; R3 is —OR3a; R3a is C1-C6 alkyl or C1-C6 haloalkyl wherein the C1-C6 alkyl and the C1-C6 haloalkyl are each substituted with one G3D; G3D is a 4-7 membered monocyclic heterocycle; and R5 is C1-C6 alkyl. In some such embodiments, R6 is hydrogen. In some such embodiments, R6 is C1-C6 alkyl or C1-C6 haloalkyl. In some such embodiments, R6 is C1-C6 alkyl. In some such embodiments, R6 is —CH3.
In one embodiment, the invention is directed to compounds wherein R3 is -G3B-L3-G3C-G3E; G3B is phenyl, 5-6 membered heteroaryl, or 4-11 membered heterocycle; each of which is optionally substituted; G3C is optionally substituted 4-11 membered heterocycle; and G3E is optionally substituted C3-C8 monocyclic cycloalkyl. In some such embodiments, R6 is hydrogen. In some such embodiments, R6 is C1-C6 alkyl or C1-C6 haloalkyl. In some such embodiments, R6 is C1-C6 alkyl. In some such embodiments, R6 is —CH3. In some such embodiments, R5 and R6 together form a C1-C6 alkylenyl or —N(Rz)—(C1-C6 alkylenyl)- wherein the N(Rz) is attached to the S(O)2 moiety of formula (I).
In one embodiment, the invention is directed to compounds wherein R1 is G1A; wherein G1A is phenyl, 5-6 membered monocyclic heteroaryl, or C3-C6 monocyclic cycloalkyl; R2 is C1-C6 alkyl, —OR2xa, or G2A; wherein G2A is an optionally substituted C3-C6 monocyclic cycloalkyl; and R3 is G3A, -G3B-L1-G3C, -G3B-L3-G3C-G3E, —(C1-C6 alkylenyl)-G3D, or —OR3a. In some such embodiments, R6 is hydrogen. In some such embodiments, R6 is C1-C6 alkyl or C1-C6 haloalkyl. In some such embodiments, R6 is C1-C6 alkyl. In some such embodiments, R6 is —CH3. In some such embodiments, R5 and R6 together form a C1-C6 alkylenyl or —N(Rz)—(C1-C6 alkylenyl)- wherein the N(Rz) is attached to the S(O)2 moiety of formula (I).
In one embodiment, the invention is directed to compounds wherein R1 is G1A; wherein G1A is phenyl, 5-6 membered monocyclic heteroaryl, or C3-C6 monocyclic cycloalkyl; R2 is C1-C6 alkyl, —OR2xa, or G2A; wherein G2A is an optionally substituted C3-C6 monocyclic cycloalkyl; R3 is G3A, -G3B-L1-G3C, -G3B-L3-G3C-G3E, —(C1-C6 alkylenyl)-G3D, or —OR3a; and R5 is C1-C6 alkyl or C1-C6 haloalkyl. In some such embodiments, R6 is hydrogen. In some such embodiments, R6 is C1-C6 alkyl or C1-C6 haloalkyl. In some such embodiments, R6 is C1-C6 alkyl. In some such embodiments, R6 is —CH3.
In one embodiment, the invention is directed to compounds wherein

    
    
        R1 is G1A, C1-C6 haloalkyl, or C1-C6 alkyl; wherein the C1-C6 haloalkyl and the C1-C6 alkyl are each optionally substituted with one G1A;
        G1A, at each occurrence, is independently phenyl, 5-6 membered monocyclic heteroaryl, 4-7 membered monocyclic heterocycle, or C3-C6 monocyclic cycloalkyl; wherein each G1A is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of R1a and G1B;
        G1B, at each occurrence, is independently 4-7 membered monocyclic heterocycle which is optionally substituted with 1, 2, 3, or 4 independently selected R1b groups;
        R2 is hydrogen, C2-C4 alkenyl, C1-C6 alkyl, C1-C6 haloalkyl, —OR2xa, —N(R2xa)(R2xb), or G2A;
        R2xa, at each occurrence, is independently C1-C6 alkyl, C1-C6 haloalkyl, or G2B;
        R2xb is hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl;
        G2A and G2B are each independently a 4-7 membered monocyclic heterocycle or a C3-C6 monocyclic cycloalkyl; wherein G2A and G2B are each optionally substituted with 1, 2, or 3 independently selected R2a groups;
        R3 is G3A, -G3B-L1-G3C, —OR3a, or —N(R3a)(R3b);
        R3a, at each occurrence, is independently G3D, C1-C6 haloalkyl, or C1-C6 alkyl; wherein the C1-C6 haloalkyl and the C1-C6 alkyl are each optionally substituted with one or two substituents independently selected from the group consisting of G3D, —OR3xa, and —N(R3xb)2;
        R3xa and R3xb, at each occurrence, are each independently hydrogen, C1-C6 haloalkyl, C1-C6 alkyl, or G3D;
        R3b is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl;
        L1 is a bond, C1-C6 alkylenyl, (C1-C6 alkylenyl)r-L2-(C1-C6 alkylenyl)s, or O—(C1-C6 alkylenyl)-C(O), wherein the left end of the L1 moiety is attached to G3B;
        L2 is O, N(Rx), C(O), N(Rx)C(O), or C(O)N(Rx); wherein each Rx is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl;
        r is 0 or 1;
        s is 0 or 1;
        G3A, G3B, and G3C and each independently C3-C11 cycloalkyl, phenyl, 5-6 membered monocyclic heteroaryl, or 4-11 membered heterocycle; wherein G3A, G3B, and G3C are each optionally substituted with 1, 2, 3, or 4 independently selected Re groups;
        G3D, at each occurrence, is independently C3-C8 monocyclic cycloalkyl or 4-7 membered monocyclic heterocycle; wherein each G3D is optionally substituted with 1, 2, 3, or 4 independently selected Re groups;
        R4 is hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl;
        R5 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, —N(R5ax)(R5bx), or G5A; wherein the C1-C6 alkyl and the C1-C6 haloalkyl are each optionally substituted with one or two substituents independently selected from the group consisting of G5A, —CN, —N3, —OR5ax, —S(O)2R5ax, —S(O)2N(R5ax)(R5bx), —N(R5ax)(R5bx), —N(R5bx)S(O)2R5cx, —N(R5bx)C(O)R5cx, —N(R5bx)C(O)N(R5ax)(R5bx), —N(R5bx)C(O)OR5cx, —C(O)R5ax, —C(O)OR5ax, —C(O)N(R5bx)S(O)2R5cx, and —C(O)N(R5ax)(R5bx);
        R5ax and R5bx, at each occurrence, are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, G5A, or —(C1-C6 alkylenyl)-G5A;
        R5cx, at each occurrence, is independently C1-C6 alkyl, C1-C6 haloalkyl, G5A, or —(C1-C6 alkylenyl)-G5A;
        G5A, at each occurrence, is independently C3-C11 cycloalkyl, phenyl, 5-6 membered monocyclic heteroaryl, or 4-11 membered heterocycle; wherein each G5A is optionally substituted with 1, 2, 3, or 4 independently selected R5a groups;
        R5a, at each occurrence, is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, oxo, G5B, —CN, NO2, —ORb, —OC(O)Rc, —OC(O)N(Rd)2, —SRb, —S(O)2Rb, —S(O)2N(Rd)2, —C(O)Rb, —C(O)ORb, —C(O)N(Rd)2, —C(O)N(Rd)S(O)2Rc, —N(Rd)2, —N(Rd)C(O)Rc, —N(Rd)S(O)2Rc, —N(Rd)C(O)O(Rb), —N(Rd)C(O)N(Rd)2, —N(Rd)S(O)2N(Rd)2, —(C1-C6 alkylenyl)-CN, —(C1-C6 alkylenyl)-G5B, —(C1-C6 alkylenyl)-ORb, —(C1-C6 alkylenyl)-OC(O)Rc, —(C1-C6 alkylenyl)-OC(O)N(Rd)2, —(C1-C6 alkylenyl)-SRb, —(C1-C6 alkylenyl)-S(O)2Rb, —(C1-C6 alkylenyl)-S(O)2N(Rd)2, —(C1-C6 alkylenyl)-C(O)Rb, —(C1-C6 alkylenyl)-C(O)ORb, —(C1-C6 alkylenyl)-C(O)N(Rd)2, —(C1-C6 alkylenyl)-C(O)N(Rd)S(O)2Rc, —(C1-C6 alkylenyl)-N(Rd)2, —(C1-C6 alkylenyl)-N(Rd)C(O)Rc, —(C1-C6 alkylenyl)-N(Rd)S(O)2Rc, —(C1-C6 alkylenyl)-N(Rd)C(O)O(Rc), —(C1-C6 alkylenyl)-N(Rd)C(O)N(Rd)2, or —(C1-C6 alkylenyl)-N(Rd)S(O)2N(Rd)2;
        Rb and Rd, at each occurrence, are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, alkoxyalkyl, G5B, or —(C1-C6 alkylenyl)-G5B;
        Rc, at each occurrence, is independently C1-C6 alkyl, C1-C6 haloalkyl, alkoxyalkyl, G5B, or —(C1-C6 alkylenyl)-G5B;
        G5B, at each occurrence, is independently C3-C6 monocyclic cycloalkyl, phenyl, 5-6 membered monocyclic heteroaryl, or 4-7 membered monocyclic heterocycle; wherein each G5B is optionally substituted with 1, 2, 3, or 4 independently selected R5b groups;
        Re, at each occurrence, is independently C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl, C1-C6 haloalkyl, halogen, oxo, —CN, —N3, NO2, —ORf, —OC(O)Rg, —OC(O)NRfRh, —SRf, —S(O)2Rf, —S(O)2NRfRh, —C(O)Rf, —C(O)ORf, —C(O)NRfRh, —C(O)N(Rh)S(O)2Rf, —N(Rf)2, —N(Rh)C(O)Rh, —N(Rh)S(O)2Rg, —N(Rh)C(O)O(Rg), —N(Rh)C(O)NRfRh, or —N(Rh)S(O)2NRfRh; wherein the C1-C6 haloalkyl and the C1-C6 alkyl are each optionally substituted with 1 or 2 substituents independently selected from the group consisting of —CN, NO2, —ORf, —OC(O)Rg, —OC(O)NRfRh, —SRf, —S(O)2Rf, —S(O)2NRfRh, —C(O)Rf, —C(O)ORf, —C(O)NRfRh, —C(O)N(Rh)S(O)2Rf, —N(Rf)2, —N(Rh)C(O)Rg, —N(Rh)S(O)2Rg, —N(Rh)C(O)O(Rg), —N(Rh)C(O)NRfRh, and —N(Rh)S(O)2NRfRh;
        Rf, at each occurrence, is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, —(C1-C6 alkylenyl)-CN, —(C1-C6 alkylenyl)-ORm, —(C1-C6 alkylenyl)-OC(O)Rn, —(C1-C6 alkylenyl)-OC(O)N(Rm)2, —(C1-C6 alkylenyl)-SRm, —(C1-C6 alkylenyl)-S(O)2Rm, —(C1-C6 alkylenyl)-S(O)2N(Rm)2, —(C1-C6 alkylenyl)-C(O)Rm, —(C1-C6 alkylenyl)-C(O)ORm, —(C1-C6 alkylenyl)-C(O)N(Rm)2, —(C1-C6 alkylenyl)-C(O)N(Rm)S(O)2Rn, —(C1-C6 alkylenyl)-N(Rm)2, —(C1-C6 alkylenyl)-N(Rm)C(O)Rn, —(C1-C6 alkylenyl)-N(Rm)S(O)2Rn, —(C1-C6 alkylenyl)-N(Rm)C(O)O(Rn), —(C1-C6 alkylenyl)-N(Rm)C(O)N(Rm)2, or —(C1-C6 alkylenyl)-N(Rm)S(O)2N(Rm)2;
        Rg, at each occurrence, is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, —(C1-C6 alkylenyl)-CN, —(C1-C6 alkylenyl)-ORm, —(C1-C6 alkylenyl)-OC(O)Rn, —(C1-C6 alkylenyl)-OC(O)N(Rm)2, —(C1-C6 alkylenyl)-SRm, —(C1-C6 alkylenyl)-S(O)2Rm, —(C1-C6 alkylenyl)-S(O)2N(Rm)2, —(C1-C6 alkylenyl)-C(O)Rm, —(C1-C6 alkylenyl)-C(O)ORm, —(C1-C6 alkylenyl)-C(O)N(Rm)2, —(C1-C6 alkylenyl)-C(O)N(Rm)S(O)2Rn, —(C1-C6 alkylenyl)-N(Rm)2, —(C1-C6 alkylenyl)-N(Rm)C(O)Rn, —(C1-C6 alkylenyl)-N(Rm)S(O)2Rn, —(C1-C6 alkylenyl)-N(Rm)C(O)O(Rn), —(C1-C6 alkylenyl)-N(Rm)C(O)N(Rm)2, or —(C1-C6 alkylenyl)-N(Rm)S(O)2N(Rm)2;
        Rh, at each occurrence, is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or —(C1-C6 alkylenyl)-ORm;
        R1a, R1b, R2a, and R5b, at each occurrence, are each independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, oxo, —CN, —NO2, —ORm, —OC(O)Rn, —OC(O)N(Rm)2, —SRm, —S(O)2Rm, —S(O)2N(Rm)2, —C(O)Rm, —C(O)ORm, —C(O)O(benzyl), —C(O)N(Rm)2, —C(O)N(Rm)S(O)2Rn, —N(Rm)2, —N(Rm)(alkoxyalkyl), —N(alkoxyalkyl)2, —N(Rm)C(O)Rn, —N(Rm)S(O)2Rn, —N(Rm)C(O)O(Rn), —N(Rm)C(O)N(Rm)2, —N(Rm)S(O)2N(Rm)2, —(C1-C6 alkylenyl)-CN, —(C1-C6 alkylenyl)-ORm, —(C1-C6 alkylenyl)-OC(O)Rn, —(C1-C6 alkylenyl)-OC(O)N(Rm)2, —(C1-C6 alkylenyl)-SRm, —(C1-C6 alkylenyl)-S(O)2Rm, —(C1-C6 alkylenyl)-S(O)2N(Rm)2, —(C1-C6 alkylenyl)-C(O)Rm, —(C1-C6 alkylenyl)-C(O)ORm, —(C1-C6 alkylenyl)-C(O)N(Rm)2, —(C1-C6 alkylenyl)-C(O)N(Rm)S(O)2Rn, —(C1-C6 alkylenyl)-N(Rm)2, —(C1-C6 alkylenyl)-N(Rm)C(O)Rn, —(C1-C6 alkylenyl)-N(Rm)S(O)2Rn, —(C1-C6 alkylenyl)-N(Rm)C(O)O(Rn), —(C1-C6 alkylenyl)-N(Rm)C(O)N(Rn)2, or —(C1-C6 alkylenyl)-N(Rm)S(O)2N(Rn)2;
        Rm, at each occurrence, is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl;
        Rn, at each occurrence, is independently C1-C6 alkyl or C1-C6 haloalkyl; and
        R6 is hydrogen.
    
    


Exemplary compounds of formula (I) include, but are not limited to:

    N-(methanesulfonyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(benzenesulfonyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-1H-pyrazzolo[3,4-b]pyridine-6-carboxamide;
    3-methyl-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-N-(trifluoromethanesulfonyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(cyclopropanesulfonyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(ethanesulfonyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(methanesulfonyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1-[3-(trifluoromethoxy)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[4-(dimethylamino)phenyl]-N-(methanesulfonyl)-1-phenyl-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(methanesulfonyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-cyclohexyl-4-[2-(dimethylamino)pyrimidin-5-yl]-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-[3-(azetidin-1-yl)phenyl]-N-(methanesulfonyl)-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-cyclohexyl-N-(methanesulfonyl)-4-[2-(morpholin-4-yl)pyrimidin-5-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-tert-butyl-1-cyclopentyl-N-(methanesulfonyl)-4-[6-(morpholin-4-yl)pyridin-3-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(methanesulfonyl)-3-methyl-1-phenyl-4-(piperidin-1-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(methanesulfonyl)-4-(4-methoxyphenyl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(ethanesulfonyl)-4-(4-methoxyphenyl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(methanesulfonyl)-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1-[3-(pyrrolidin-1-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[4-(dimethylamino)phenyl]-N-(methanesulfonyl)-1-(6-methoxypyridin-3-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-(3-chloro-4-methylphenyl)-N-(methanesulfonyl)-4-(4-methoxyphenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(ethanesulfonyl)-3-methyl-1-phenyl-4-(piperidin-1-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(methanesulfonyl)-4-[2-(morpholin-4-yl)pyrimidin-5-yl]-1-phenyl-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-(2,4-difluorophenyl)-N-(methanesulfonyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-cyclohexyl-4-[6-(dimethylamino)pyridin-3-yl]-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-(3,5-difluorophenyl)-N-(methanesulfonyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-(3,5-dimethylphenyl)-N-(methanesulfonyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-(3,4-difluorophenyl)-N-(methanesulfonyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[4-(dimethylamino)phenyl]-N-(methanesulfonyl)-3-methyl-1-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(methanesulfonyl)-4-(4-methoxyphenyl)-3-methyl-1-(3-methylphenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(ethanesulfonyl)-4-(4-methoxyphenyl)-3-methyl-1-(3-methylphenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[2-(dimethylamino)pyrimidin-5-yl]-N-(methanesulfonyl)-1-[3-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[2-(dimethylamino)pyrimidin-5-yl]-N-(ethanesulfonyl)-1-[3-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[6-(dimethylamino)pyridin-3-yl]-N-(methanesulfonyl)-1-[3-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[6-(dimethylamino)pyridin-3-yl]-N-(ethanesulfonyl)-1-[3-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[4-(dimethylamino)phenyl]-N-(methanesulfonyl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(methanesulfonyl)-4-[6-(morpholin-4-yl)pyridin-3-yl]-1-phenyl-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(ethanesulfonyl)-4-[6-(morpholin-4-yl)pyridin-3-yl]-1-phenyl-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(methanesulfonyl)-1-[3-(3-methoxyazetidin-1-yl)phenyl]-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(methanesulfonyl)-3-methyl-4-[6-(morpholin-4-yl)pyridin-3-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-(4,4-difluorocyclohexyl)-N-(methanesulfonyl)-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(methanesulfonyl)-4-[4-(morpholin-4-yl)phenyl]-1-(oxan-3-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(ethanesulfonyl)-4-[4-(morpholin-4-yl)phenyl]-1-(oxan-3-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-{4-[3-(dimethylamino)azetidin-1-yl]phenyl}-N-(methanesulfonyl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-{4-[3-(dimethylamino)azetidin-1-yl]phenyl}-N-(ethanesulfonyl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-[3-(3,3-dimethylazetidin-1-yl)phenyl]-N-(methanesulfonyl)-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-cyclohexyl-N-(methanesulfonyl)-4-[6-(morpholin-4-yl)pyridin-3-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-cyclohexyl-N-(ethanesulfonyl)-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-[3-(3-fluoropyrrolidin-1-yl)phenyl]-N-(methanesulfonyl)-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-cyclohexyl-N-(methanesulfonyl)-3-methyl-4-[6-(morpholin-4-yl)pyridin-3-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-cyclohexyl-N-(ethanesulfonyl)-3-methyl-4-[6-(morpholin-4-yl)pyridin-3-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-cyclohexyl-4-[2-(dimethylamino)pyrimidin-5-yl]-N-(methanesulfonyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-cyclohexyl-4-[2-(dimethylamino)pyrimidin-5-yl]-N-(ethanesulfonyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-cyclohexyl-N-(methanesulfonyl)-4-{6-[methyl(oxan-4-yl)amino]pyridin-3-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    methyl 3-{1-cyclohexyl-4-[2-(dimethylamino)pyrimidin-5-yl]-6-[(ethanesulfonyl)carbamoyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}azetidine-1-carboxylate;
    1-[3-(dimethylamino)phenyl]-N-(methanesulfonyl)-4-[6-(morpholin-4-yl)pyridin-3-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-[3-(dimethylamino)phenyl]-N-(ethanesulfonyl)-4-[6-(morpholin-4-yl)pyridin-3-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-cyclopentyl-4-[6-(dimethylamino)pyridin-3-yl]-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-cyclopentyl-4-[6-(dimethylamino)pyridin-3-yl]-N-(ethanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(methanesulfonyl)-3-methyl-4-[6-(morpholin-4-yl)pyridin-3-yl]-1-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(ethanesulfonyl)-3-methyl-4-[6-(morpholin-4-yl)pyridin-3-yl]-1-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-[3-(dimethylamino)phenyl]-N-(methanesulfonyl)-4-[2-(morpholin-4-yl)pyrimidin-5-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-(2,4-difluorophenyl)-N-(methanesulfonyl)-3-methyl-4-[6-(morpholin-4-yl)pyridin-3-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-(2,4-difluorophenyl)-N-(ethanesulfonyl)-3-methyl-4-[6-(morpholin-4-yl)pyridin-3-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-[3-(dimethylamino)phenyl]-N-(ethanesulfonyl)-4-[2-(morpholin-4-yl)pyrimidin-5-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(methanesulfonyl)-4-{6-[(2-methoxyethyl)(methyl)amino]pyridin-3-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-cyclohexyl-4-[6-(3,3-difluoropyrrolidin-1-yl)pyridin-3-yl]-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-(3-chlorophenyl)-N-(methanesulfonyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-(3-chlorophenyl)-N-(ethanesulfonyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-(3-fluorophenyl)-N-(methanesulfonyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(ethanesulfonyl)-1-(3-fluorophenyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(methanesulfonyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1-[4-(trifluoromethoxy)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(ethanesulfonyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1-[4-(trifluoromethoxy)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-3-cyclobutyl-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(methanesulfonyl)-1-(3-methoxyphenyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(ethanesulfonyl)-1-(3-methoxyphenyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(methanesulfonyl)-4-{6-[methyl(oxan-4-yl)amino]pyridin-3-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(methanesulfonyl)-4-{4-[(2-methoxyethyl)(methyl)amino]phenyl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(methanesulfonyl)-1-{3-[(2-methoxyethyl)(methyl)amino]phenyl}-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-[3-(dimethylamino)phenyl]-4-[2-(dimethylamino)pyrimidin-5-yl]-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-[3-(dimethylamino)phenyl]-4-[2-(dimethylamino)pyrimidin-5-yl]-N-(ethanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-(4-acetamidophenyl)-1-cyclohexyl-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[4-(4-cyanopiperidin-1-yl)phenyl]-1-cyclohexyl-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[4-(4-cyanopiperidin-1-yl)phenyl]-1-[3-(dimethylamino)phenyl]-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-[3-(dimethylamino)phenyl]-N-(methanesulfonyl)-4-{4-[(2-methoxyethyl)(methyl)amino]phenyl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-1-[3-(dimethylamino)phenyl]-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-[3-(dimethylamino)phenyl]-N-(methanesulfonyl)-4-{6-[(2-methoxyethyl)(methyl)amino]pyridin-3-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-N-(methanesulfonyl)-1-[3-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(methanesulfonyl)-4-{6-[(2-methoxyethyl)(methyl)amino]pyridin-3-yl}-1-[3-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(methanesulfonyl)-4-{6-[methyl(oxan-4-yl)amino]pyridin-3-yl}-1-[3-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(methanesulfonyl)-4-{4-[(2-methoxyethyl)(methyl)amino]phenyl}-1-[3-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-[3-(dimethylamino)phenyl]-N-(methanesulfonyl)-4-{6-[methyl(oxan-4-yl)amino]pyridin-3-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-cyclohexyl-N-(ethanesulfonyl)-4-{6-[methyl(oxan-4-yl)amino]pyridin-3-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-[3-(dimethylamino)phenyl]-N-(methanesulfonyl)-4-{2-[methyl(oxan-4-yl)amino]pyrimidin-5-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-cyclohexyl-3-cyclopropyl-4-[6-(dimethylamino)pyridin-3-yl]-N-(ethanesulfonyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-cyclohexyl-4-[6-(2,6-dimethylmorpholin-4-yl)pyridin-3-yl]-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-cyclohexyl-4-[6-(2,2-dimethylmorpholin-4-yl)pyridin-3-yl]-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[2-(4-cyanopiperidin-1-yl)pyrimidin-5-yl]-1-[3-(dimethylamino)phenyl]-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-[3-(dimethylamino)phenyl]-N-(methanesulfonyl)-4-{4-[methyl(oxan-4-yl)amino]phenyl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(methanesulfonyl)-4-{4-[methyl(oxan-4-yl)amino]phenyl}-1-[3-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[6-(4-cyano-4-methylpiperidin-1-yl)pyridin-3-yl]-1-cyclohexyl-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[2-(4-cyanopiperidin-1-yl)pyrimidin-5-yl]-N-(methanesulfonyl)-1-[3-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-{4-[3-(dimethylamino)pyrrolidin-1-yl]phenyl}-N-(methanesulfonyl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(methanesulfonyl)-1-(3-methylphenyl)-4-(piperidin-1-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(ethanesulfonyl)-1-(3-methylphenyl)-4-(piperidin-1-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[4-(4-cyanopiperidin-1-yl)phenyl]-3-cyclobutyl-1-cyclohexyl-N-(methanesulfonyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-3-cyclobutyl-1-cyclohexyl-N-(methanesulfonyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-[3-(3-hydroxyazetidin-1-yl)phenyl]-N-(methanesulfonyl)-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-cyclohexyl-N-(methanesulfonyl)-4-[6-(3-methoxypyrrolidin-1-yl)pyridin-3-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    methyl 3-{4-(4-acetamidophenyl)-1-(3,5-difluorophenyl)-6-[(methanesulfonyl)carbamoyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}azetidine-1-carboxylate;
    1-cyclohexyl-4-[6-(3-fluoropiperidin-1-yl)pyridin-3-yl]-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(methanesulfonyl)-4-{4-[(2-methoxyethyl)(methyl)amino]phenyl}-3-(propan-2-yl)-1-[3-(pyrrolidin-1-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(methanesulfonyl)-4-{4-[methyl(oxan-4-yl)amino]phenyl}-3-(propan-2-yl)-1-[3-(pyrrolidin-1-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(methanesulfonyl)-4-{4-[methyl(oxan-4-yl)amino]phenyl}-1-[3-(pyrrolidin-1-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(ethanesulfonyl)-4-[2-(morpholin-4-yl)pyrimidin-5-yl]-1-phenyl-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-(2,4-difluorophenyl)-N-(ethanesulfonyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-(3-chloro-4-methylphenyl)-N-(ethanesulfonyl)-4-(4-methoxyphenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-(3,5-dimethylphenyl)-N-(ethanesulfonyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-(3,4-difluorophenyl)-N-(ethanesulfonyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(methanesulfonyl)-4-(4-methoxypiperidin-1-yl)-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(ethanesulfonyl)-4-(4-methoxypiperidin-1-yl)-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[2-(4-cyanopiperidin-1-yl)pyrimidin-5-yl]-1-cyclohexyl-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-cyclohexyl-N-(methanesulfonyl)-4-{2-[(2-methoxyethyl)(methyl)amino]pyrimidin-5-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-{6-[bis(2-methoxyethyl)amino]pyridin-3-yl}-1-cyclohexyl-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-cyclohexyl-N-(methanesulfonyl)-4-{6-[methyl(oxolan-3-yl)amino]pyridin-3-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-cyclohexyl-N-(methanesulfonyl)-4-{2-[methyl(oxan-4-yl)amino]pyrimidin-5-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-N-(methanesulfonyl)-3-(propan-2-yl)-1-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-[6-(dimethylamino)pyridin-2-yl]-N-(methanesulfonyl)-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(methanesulfonyl)-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1-[3-(trifluoromethoxy)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-(3,4-difluorophenyl)-N-(methanesulfonyl)-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(methanesulfonyl)-4-[4-(morpholin-4-yl)phenyl]-1-[6-(morpholin-4-yl)pyridin-2-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-(2,6-difluoro-4-methoxyphenyl)-1-(3-fluoro-5-methoxyphenyl)-N-(methanesulfonyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[4-(4-cyanopiperidin-1-yl)phenyl]-1-(3,5-difluorophenyl)-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[4-(4-cyanopiperidin-1-yl)phenyl]-1-(3-fluorophenyl)-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(methanesulfonyl)-4-{4-[(2-methoxyethyl)(methyl)amino]phenyl}-3-(propan-2-yl)-1-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(methanesulfonyl)-4-{6-[methyl(oxan-4-yl)amino]pyridin-3-yl}-3-(propan-2-yl)-1-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-(4-fluorophenyl)-N-(methanesulfonyl)-4-{2-[methyl(oxan-4-yl)amino]pyrimidin-5-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[4-(4-cyanopiperidin-1-yl)phenyl]-N-(methanesulfonyl)-3-(propan-2-yl)-1-[3 (trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(methanesulfonyl)-4-[4-(morpholin-4-yl)phenyl]-1-[2-(morpholin-4-yl)pyridin-4-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(methanesulfonyl)-3-(1-methylcyclobutyl)-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(ethanesulfonyl)-3-(1-methylcyclobutyl)-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[2-(4-cyanopiperidin-1-yl)pyrimidin-5-yl]-1-(2,4-difluorophenyl)-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-1-(2,4-difluorophenyl)-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[4-(4-cyanopiperidin-1-yl)phenyl]-1-(2,4-difluorophenyl)-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(methanesulfonyl)-4-(4-methoxypiperidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(1,1-dioxo-1λ6-thiolane-3-sulfonyl)-4-(4-methoxypiperidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-[3-(dimethylamino)phenyl]-N-(methanesulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-N-(methanesulfonyl)-1-(oxan-3-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(2-methoxyethanesulfonyl)-4-(4-methoxypiperidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-(4-methoxypiperidin-1-yl)-1-phenyl-N-(3,3,3-trifluoropropane-1-sulfonyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(methanesulfonyl)-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-(1,1-difluoro-5-azaspiro[2.4]heptan-5-yl)-N-(methanesulfonyl)-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-cyclohexyl-N-(methanesulfonyl)-4-(4-methoxypiperidin-1-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(methanesulfonyl)-1-phenyl-4-{4-[(propan-2-yl)oxy]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(methanesulfonyl)-1-phenyl-4-(4-propoxypiperidin-1-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(methanesulfonyl)-4-[3-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(methanesulfonyl)-4-{4-[2-oxo-2-(pyrrolidin-1-yl)ethoxy]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-[3-(dimethylamino)phenyl]-N-(methanesulfonyl)-4-(4-methoxypiperidin-1-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(methanesulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-[3-(dimethylamino)phenyl]-N-(methanesulfonyl)-4-(piperidin-1-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-N-(methanesulfonyl)-3-(propan-2-yl)-1-[2-(pyrrolidin-1-yl)pyridin-4-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(methanesulfonyl)-4-(1-oxa-7-azaspiro[3.5]nonan-7-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-(4-cyanopiperidin-1-yl)-1-[3-(dimethylamino)phenyl]-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(methanesulfonyl)-4-[4-(2-methoxyethyl)piperidin-1-yl]-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(methanesulfonyl)-4-(3-methoxypiperidin-1-yl)-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(ethanesulfonyl)-4-(3-methoxypiperidin-1-yl)-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[4-(fluoromethyl)piperidin-1-yl]-N-(methanesulfonyl)-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(methanesulfonyl)-4-[4-(methanesulfonyl)piperidin-1-yl]-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(methanesulfonyl)-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-(4-fluorophenyl)-N-(methanesulfonyl)-4-(4-methoxypiperidin-1-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-(4-fluorophenyl)-N-(methanesulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[4-(4-cyanopiperidin-1-yl)phenyl]-N-(methanesulfonyl)-3-(propan-2-yl)-1-[2-(pyrrolidin-1-yl)pyridin-4-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(methanesulfonyl)-4-[(2-methoxyethyl)(methyl)amino]-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(methanesulfonyl)-1-(3-methylphenyl)-4-(8-oxa-2-azaspiro[4.5]decan-2-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-(4-butoxypiperidin-1-yl)-1-(4-fluorophenyl)-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-(4-fluorophenyl)-N-(methanesulfonyl)-4-(4-methoxy-4-methylpiperidin-1-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    2-[(2-{[3-cyclobutyl-4-(4-methoxypiperidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carbonyl]sulfamoyl}ethyl)carbamoyl]benzoic acid;
    1-(4-fluorophenyl)-N-(methanesulfonyl)-4-[4-(2-methylpropoxy)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-(4-methoxypiperidin-1-yl)-1-phenyl-N-(2,2,2-trifluoroethanesulfonyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-(4-fluorophenyl)-N-(methanesulfonyl)-4-(1-oxa-7-azaspiro[3.5]nonan-7-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[3-(difluoromethyl)piperidin-1-yl]-1-(4-fluorophenyl)-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-(4-fluorophenyl)-N-(methanesulfonyl)-4-(6-oxa-2-azaspiro[3.5]nonan-2-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-(4-fluorophenyl)-N-(methanesulfonyl)-4-(1-oxa-8-azaspiro[4.5]decan-8-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-(cyclohexylmethoxy)-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(methanesulfonyl)-1-phenyl-4-(piperidin-1-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(methanesulfonyl)-4-[4-(2-methoxyethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-(2-azaspiro[3.4]octan-2-yl)-3-cyclobutyl-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(methanesulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-(3-azabicyclo[3.1.0]hexan-3-yl)-3-cyclobutyl-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(methanesulfonyl)-4-(4-methoxypiperidin-1-yl)-1-[2-(morpholin-4-yl)pyridin-4-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(methanesulfonyl)-4-(4-methoxypiperidin-1-yl)-3-(propan-2-yl)-1-[2-(pyrrolidin-1-yl)pyridin-4-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-3-cyclobutyl-N-(methanesulfonyl)-1-[2-(pyrrolidin-1-yl)pyridin-4-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(methanesulfonyl)-4-[4-(methanesulfonyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-(4-cyanopiperidin-1-yl)-3-cyclobutyl-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-(2-azaspiro[3.5]nonan-2-yl)-3-cyclobutyl-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(methanesulfonyl)-4-[3-(methoxymethyl)azetidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-N-(methanesulfonyl)-3-(cis-3-methoxycyclobutyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-3-(3,3-difluorocyclobutyl)-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-3-(3,3-dimethylcyclobutyl)-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-3-(3-fluorocyclobutyl)-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(methanesulfonyl)-4-[2-(oxan-4-yl)ethoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-[(2S)-2-fluoro-2-(oxan-4-yl)ethoxy]-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(methanesulfonyl)-4-[(oxan-4-yl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-3-cyclobutyl-N-(methanesulfonyl)-1-[2-(morpholin-4-yl)pyridin-4-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-(1,1-difluoro-5-azaspiro[2.4]heptan-5-yl)-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(methanesulfonyl)-4-(5-oxa-2-azaspiro[3.5]nonan-2-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(methanesulfonyl)-4-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-(5-azaspiro[2.5]octan-5-yl)-3-cyclobutyl-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(methanesulfonyl)-4-[(2-methoxyethyl)(methyl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-(4-methoxypiperidin-1-yl)-N-(oxane-4-sulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    benzyl 4-{[3-cyclobutyl-4-(4-methoxypiperidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carbonyl]sulfamoyl}piperidine-1-carboxylate;
    4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-3-(cis-3-fluorocyclobutyl)-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-3-(trans-3-fluorocyclobutyl)-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(methanesulfonyl)-4-[(cis-4-methoxycyclohexyl)oxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(methanesulfonyl)-4-[(trans-4-methoxycyclohexyl)oxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-{4-[(benzyloxy)methyl]piperidin-1-yl}-3-cyclobutyl-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-(2-azaspiro[3.3]heptan-2-yl)-3-cyclobutyl-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    methyl 5-{3-cyclobutyl-6-[(methanesulfonyl)carbamoyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl}octahydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate;
    4-(1-acetyl octahydro-5H-pyrrolo[3,2-c]pyri din-5-yl)-3-cyclobutyl-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(methanesulfonyl)-4-(4-methoxypiperidin-1-yl)-1-[6-(morpholin-4-yl)pyridin-2-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-cyclohexyl-N-(methanesulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-{4-[(1S)-2-(dimethylamino)-1-fluoroethyl]piperidin-1-yl}-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-[4-(fluoromethyl)piperidin-1-yl]-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-(4-fluorophenyl)-N-(methanesulfonyl)-4-[4-(2-methoxypropan-2-yl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-(3-azaspiro[5.5]undecan-3-yl)-3-cyclobutyl-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-(3,4-difluorophenyl)-N-(ethanesulfonyl)-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(ethanesulfonyl)-1-(3-fluorophenyl)-4-{6-[methyl(oxan-4-yl)amino]pyridin-3-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(cyclopropanesulfonyl)-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(2-methoxyethanesulfonyl)-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-N-(methanesulfonyl)-1-[2-(morpholin-4-yl)pyridin-4-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-[4-(cyclopentyloxy)piperidin-1-yl]-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-[4-(cyclohexyloxy)piperidin-1-yl]-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-[4-(cyclopropylmethoxy)piperidin-1-yl]-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(2-methoxyethanesulfonyl)-4-(4-methoxyphenyl)-3-methyl-1-(2-methylpropyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(2-methoxyethanesulfonyl)-4-[4-(morpholin-4-yl)phenyl]-1-(oxolan-3-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(2-methoxyethanesulfonyl)-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(2-methoxyethanesulfonyl)-4-(4-methoxyphenyl)-3-methyl-1-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-cyclopropyl-N-(2-methoxyethanesulfonyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-(4-fluorophenyl)-N-(2-methoxyethanesulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-[(2R)-2-fluoro-2-(oxan-4-yl)ethoxy]-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-[(3,3-difluorocyclopentyl)methoxy]-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-cyclohexyl-N-(cyclopropanesulfonyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-(4-cyanopiperidin-1-yl)-1-(4-fluorophenyl)-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(methanesulfonyl)-4-[4-(1-methoxyethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(methanesulfonyl)-1-phenyl-4-[4-(1,1,1-trifluoro-2-methoxypropan-2-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-[2-(1,1-dioxo-1λ6,4-thiazinan-4-yl)ethoxy]-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-[4-(hydroxymethyl)piperidin-1-yl]-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-N-(1-methyl-1H-pyrazole-4-sulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-{6-[bis(2-methoxyethyl)amino]pyridin-3-yl}-3-cyclobutyl-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(methanesulfonyl)-4-[4-methoxy-4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(methanesulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1-[2-(morpholin-4-yl)pyridin-4-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(2-methoxyethanesulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1-[2-(morpholin-4-yl)pyridin-4-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(1,2-dimethyl-1H-imidazole-4-sulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-cyclohexyl-N-(2-methoxyethanesulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-{6-[bis(2-methoxyethyl)amino]pyridin-3-yl}-N-(methanesulfonyl)-1-[2-(morpholin-4-yl)pyridin-4-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-N-(1H-pyrazole-4-sulfonyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(methanesulfonyl)-4-[(3-methyloxetan-3-yl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-{4-[(1,1-dioxo-1λ6,4-thiazinan-4-yl)methyl]-4-methoxypiperidin-1-yl}-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(2-methoxyethanesulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-N-(methanesulfonyl)-3-(trans-3-methylcyclobutyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-N-(methanesulfonyl)-1-phenyl-3-[(piperidin-4-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    tert-butyl 4-({4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-6-[(methanesulfonyl)carbamoyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridin-3-yl}oxy)piperidine-1-carboxylate;
    3-cyclobutyl-N-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethanesulfonyl]-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(2-aminoethanesulfonyl)-3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-(cyclobutylmethyl)-N-(methanesulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-(cyclobutylmethyl)-N-(2-methoxyethanesulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(methanesulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1-(2-methylpropyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(2-methoxyethanesulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1-(2-methylpropyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-(4-fluorophenyl)-N-(methanesulfonyl)-3-(propan-2-yl)-4-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-N-[2-(morpholin-4-yl)ethanesulfonyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(methanesulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(2-methoxyethanesulfonyl)-4-[(3-methyloxetan-3-yl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(methanesulfonyl)-1-phenyl-4-[4-(propan-2-yl)piperazin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(2-methoxyethanesulfonyl)-1-phenyl-4-[4-(propan-2-yl)piperazin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-(4-fluorophenyl)-4-[4-(methoxymethyl)piperidin-1-yl]-N-[3-(morpholin-4-yl)propane-1-sulfonyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-[2-(dimethylamino)ethanesulfonyl]-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[(1-acetyl-4-fluoropiperidin-4-yl)methoxy]-3-cyclobutyl-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-N-(2-methoxyethanesulfonyl)-3-[(oxolan-3-yl)oxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-N-(2-methoxyethanesulfonyl)-3-(trans-3-methylcyclobutyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-N-(methanesulfonyl)-3-[(oxolan-3-yl)oxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-[3-(dimethylamino)phenyl]-N-(methanesulfonyl)-4-[(oxan-4-yl)methoxy]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(methanesulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1-[2-(morpholin-4-yl)pyrimidin-4-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-(4-cyclobutylpiperazin-1-yl)-1-(4-fluorophenyl)-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(methanesulfonyl)-4-[3-(morpholin-4-yl)propoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-[(3,3-difluoro-1-methylcyclobutyl)methoxy]-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(methanesulfonyl)-4-[(oxolan-2-yl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-(4-fluorophenyl)-N-(methanesulfonyl)-4-[(oxan-4-yl)methoxy]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-(4-fluorophenyl)-N-(methanesulfonyl)-4-[2-(oxan-4-yl)ethoxy]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-N-(1-methyl-1H-imidazole-4-sulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(3,5-dimethyl-1,2-oxazole-4-sulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    methyl 3-({3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carbonyl}sulfamoyl)propanoate;
    3-({3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carbonyl}sulfamoyl)propanoic acid;
    N-[3-(dimethylamino)propane-1-sulfonyl]-1-(4-fluorophenyl)-4-[4-(methoxymethyl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-(4-fluorophenyl)-4-[4-(methoxymethyl)piperidin-1-yl]-3-(propan-2-yl)-N-[3-(pyrrolidin-1-yl)propane-1-sulfonyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-(4-fluorophenyl)-N-(methanesulfonyl)-4-[3-(morpholin-4-yl)propoxy]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-(4-fluorophenyl)-N-(methanesulfonyl)-4-[(3-methyloxetan-3-yl)methoxy]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(methanesulfonyl)-4-[4-(2-methoxypropan-2-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-(4-fluorophenyl)-N-(methanesulfonyl)-4-[(oxolan-2-yl)methoxy]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[(1-acetylpiperidin-4-yl)methoxy]-3-cyclobutyl-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    methyl 4-[({3-cyclobutyl-6-[(methanesulfonyl)carbamoyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl}oxy)methyl]piperidine-1-carboxylate;
    3-cyclobutyl-N-[3-(dimethylamino)-3-oxopropane-1-sulfonyl]-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[3-(dimethylamino)propoxy]-1-(4-fluorophenyl)-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-N-(methanesulfonyl)-3-[(oxetan-3-yl)oxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-(4-fluorophenyl)-N-(methanesulfonyl)-4-[(2-methoxyethyl)(methyl)amino]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-[3-(azetidin-1-yl)propane-1-sulfonyl]-1-(4-fluorophenyl)-4-[4-(methoxymethyl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-[3-(dimethylamino)propoxy]-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-(4-fluorophenyl)-4-[4-(2-hydroxypropan-2-yl)piperidin-1-yl]-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-(4-fluorophenyl)-N-(methanesulfonyl)-4-[2-(1-methylpiperidin-2-yl)ethoxy]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[(3,3-difluoro-1-methylcyclobutyl)methoxy]-1-(4-fluorophenyl)-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-(4-fluorophenyl)-N-(methanesulfonyl)-4-[3-(piperidin-1-yl)propoxy]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[(1-acetyl-4-fluoropiperidin-4-yl)methoxy]-1-(4-fluorophenyl)-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-(4-fluorophenyl)-N-(methanesulfonyl)-4-{2-[(oxetan-3-yl)(propan-2-yl)amino]ethoxy}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-(4-fluorophenyl)-N-(methanesulfonyl)-3-(propan-2-yl)-4-{[4-(propan-2-yl)morpholin-3-yl]methoxy}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[(1,3-dimethoxypropan-2-yl)oxy]-1-(4-fluorophenyl)-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[(1,4-dioxan-2-yl)methoxy]-1-(4-fluorophenyl)-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-(4-fluorophenyl)-N-(methanesulfonyl)-4-{2-[(oxetan-3-yl)oxy]ethoxy}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(methanesulfonyl)-1-phenyl-4-[3-(piperidin-1-yl)propoxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(2-methoxyethanesulfonyl)-4-[(oxan-4-yl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-(4-fluorophenyl)-N-(methanesulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-[4-(2-hydroxypropan-2-yl)piperidin-1-yl]-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-(4-fluorophenyl)-N-(methanesulfonyl)-4-[(oxan-4-yl)methoxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[4-(dimethylamino)piperidin-1-yl]-1-(4-fluorophenyl)-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-(4-fluorophenyl)-N-(methanesulfonyl)-4-(1′-methyl[4,4′-bipiperidin]-1-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[(1-acetylpiperidin-4-yl)methoxy]-1-(4-fluorophenyl)-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    methyl 4-({[1-(4-fluorophenyl)-6-[(methanesulfonyl)carbamoyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl]oxy}methyl)piperidine-1-carboxylate;
    3-cyclobutyl-N-(methanesulfonyl)-4-[2-(1-methylpiperidin-2-yl)ethoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-[(1,3-dimethoxypropan-2-yl)oxy]-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(methanesulfonyl)-4-{2-[(oxetan-3-yl)(propan-2-yl)amino]ethoxy}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[4-(cyanomethyl)-4-hydroxypiperidin-1-yl]-3-cyclobutyl-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-(4-azidophenyl)-N-(3-azidopropane-1-sulfonyl)-1-[3-(dimethylamino)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(methanesulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(methanesulfonyl)-1-phenyl-4-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(2-methoxyethanesulfonyl)-1-phenyl-4-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(methanesulfonyl)-4-{4-[2-(morpholin-4-yl)ethyl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    rac-4-[(3aR,7aS)-1-acetyloctahydro-5H-pyrrolo[3,2-c]pyridin-5-yl]-3-cyclobutyl-N-[3-(morpholin-4-yl)propane-1-sulfonyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(cyclopropanesulfonyl)-4-[(oxan-4-yl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(dimethylsulfamoyl)-4-[(oxan-4-yl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(ethanesulfonyl)-4-[(oxan-4-yl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(methanesulfonyl)-1-[2-(morpholin-4-yl)pyridin-4-yl]-4-[(oxan-4-yl)methoxy]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    ethyl 4-[1-(4-fluorophenyl)-6-[(methanesulfonyl)carbamoyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl]piperazine-1-carboxylate;
    1-(4-fluorophenyl)-N-(methanesulfonyl)-4-(3-methyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-8-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-(4-fluorophenyl)-N-(methanesulfonyl)-3-(propan-2-yl)-4-[3-(trifluoromethyl)piperazin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-(4-fluorophenyl)-N-(methanesulfonyl)-4-[4-(2-methoxyethyl)piperazin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-(2,4-dioxo-1,3,8-triazaspiro[4.5]decan-8-yl)-1-(4-fluorophenyl)-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[4-(ethoxymethyl)-4-fluoropiperidin-1-yl]-1-(4-fluorophenyl)-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-{4-fluoro-4-[(2-methoxyethoxy)methyl]piperidin-1-yl}-1-(4-fluorophenyl)-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[(3R,4R)-3-fluoro-4-hydroxypiperidin-1-yl]-1-(4-fluorophenyl)-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[4-fluoro-4-(methoxymethyl)piperidin-1-yl]-1-(4-fluorophenyl)-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-{3-fluoro-3-[(2-methoxyethoxy)methyl]piperidin-1-yl}-1-(4-fluorophenyl)-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-[3-(morpholin-4-yl)propane-1-sulfonyl]-4-[(oxan-4-yl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-([1,4′-bipiperidin]-1′-yl)-1-(4-fluorophenyl)-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-[(3R)-3-(hydroxymethyl)piperidin-1-yl]-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-[(3R)-3-(hydroxymethyl)piperidin-1-yl]-N-[3-(morpholin-4-yl)propane-1-sulfonyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-[(oxan-4-yl)methoxy]-1-phenyl-N-[4-(pyrrolidin-1-yl)piperidine-1-sulfonyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-[(2S)-2-(4-methylpiperazine-1-carbonyl)pyrrolidine-1-sulfonyl]-4-[(oxan-4-yl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-([1,4′-bipiperidine]-1′-sulfonyl)-3-cyclobutyl-4-[(oxan-4-yl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-[methyl(propyl)sulfamoyl]-4-[(oxan-4-yl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-[ethyl(propyl)sulfamoyl]-4-[(oxan-4-yl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    ethyl 4-[({3-cyclobutyl-4-[(oxan-4-yl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carbonyl}sulfamoyl)amino]piperidine-1-carboxylate;
    N-(4-acetyl-1,4-diazepane-1-sulfonyl)-3-cyclobutyl-4-[(oxan-4-yl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(morpholine-4-sulfonyl)-4-[(oxan-4-yl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-[4-(morpholin-4-yl)piperidine-1-sulfonyl]-4-[(oxan-4-yl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-[4-(4-methylpiperazine-1-carbonyl)piperidine-1-sulfonyl]-4-[(oxan-4-yl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(4-methylpiperazine-1-sulfonyl)-4-[(oxan-4-yl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(2-methylpropane-2-sulfonyl)-4-[(oxan-4-yl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-(4-azidophenyl)-N-(but-3-yne-1-sulfonyl)-1-[3-(dimethylamino)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(cyanomethanesulfonyl)-3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-([1,4′-bipiperidin]-1′-yl)-3-cyclobutyl-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(2-hydroxyethanesulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(3-hydroxypropane-1-sulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-N-(piperidine-4-sulfonyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-N-(oxolane-3-sulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-(2,6-dimethylpyridin-4-yl)-N-(methanesulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-(1,1-dioxo-1λ6,4-thiazinan-4-yl)-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-N-[2-(1H-pyrazol-1-yl)ethanesulfonyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    benzyl [2-({3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carbonyl}sulfamoyl)ethyl]carbamate;
    3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-N-(1-methylcyclopropane-1-sulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-N-(2-methylpropane-1-sulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    methyl ({3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carbonyl}sulfamoyl)acetate;
    benzyl 3-({3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carbonyl}sulfamoyl)pyrrolidine-1-carboxylate;
    tert-butyl 4-[1-(4-fluorophenyl)-6-[(methanesulfonyl)carbamoyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl]piperidine-1-carboxylate;
    3-cyclobutyl-N-(dimethyl sulfamoyl)-1-(4-fluorophenyl)-4-{4-[2-(methoxymethyl)morpholin-4-yl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(morpholine-4-sulfonyl)-1-phenyl-4-{4-[(pyrrolidin-1-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-(4-methoxy[1,4′-bipiperidin]-1′-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-{4-[4-(propan-2-yl)piperazin-1-yl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(morpholine-4-sulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(2-amino-2-oxoethanesulfonyl)-3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(methanesulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1-(2-methoxypyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(2-acetamidoethanesulfonyl)-3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-N-(pyrrolidine-3-sulfonyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-N-[4-(pyrrolidin-1-yl)piperidine-1-sulfonyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-N-[(2S)-2-(4-methylpiperazine-1-carbonyl)pyrrolidine-1-sulfonyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-N-{4-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]piperidine-1-sulfonyl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-N-[methyl(propyl)sulfamoyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-[ethyl(propyl)sulfamoyl]-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    ethyl 4-[({3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carbonyl}sulfamoyl)amino]piperidine-1-carboxylate;
    N-(4-acetyl-1,4-diazepane-1-sulfonyl)-3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-N-{4-[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]piperidine-1-sulfonyl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-N-(morpholine-4-sulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-N-[4-(morpholin-4-yl)piperidine-1-sulfonyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-N-[4-(4-methylpiperazine-1-carbonyl)piperidine-1-sulfonyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(4-fluoropiperidine-1-sulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-N-(4-methylpiperazine-1-sulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(cyclopropanesulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(dimethylsulfamoyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(ethanesulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-cyclohexyl-N-(methanesulfonyl)-4-{4-[(morpholin-4-yl)methyl]phenyl}-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-cyclohexyl-N-(2-methoxyethanesulfonyl)-4-{4-[(morpholin-4-yl)methyl]phenyl}-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-cyclohexyl-N-(dimethyl sulfamoyl)-4-{4-[(morpholin-4-yl)methyl]phenyl}-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-(4-fluorophenyl)-N-(2-methoxyethanesulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(dimethyl sulfamoyl)-1-(4-fluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(dimethyl sulfamoyl)-1-(4-fluorophenyl)-4-{4-[(morpholin-4-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-(4-fluorophenyl)-N-(methanesulfonyl)-4-{4-[(morpholin-4-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-(4-fluorophenyl)-N-(methanesulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(dimethyl sulfamoyl)-1-(4-fluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(ethanesulfonyl)-1-(4-fluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(cyclopropanesulfonyl)-1-(4-fluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-(4-fluorophenyl)-N-(2-methoxyethanesulfonyl)-4-{4-[2-(morpholin-4-yl)ethyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(dimethyl sulfamoyl)-1-(4-fluorophenyl)-4-{4-[2-(morpholin-4-yl)ethyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-[(1,4-dioxan-2-yl)methanesulfonyl]-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-cyclohexyl-N-(methanesulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-cyclohexyl-N-(2-methoxyethanesulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-cyclohexyl-N-(dimethyl sulfamoyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-(4-fluorophenyl)-N-(methanesulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-cyclohexyl-N-(methanesulfonyl)-4-[4-(4-methylpiperazine-1-carbonyl)phenyl]-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-cyclohexyl-N-(dimethylsulfamoyl)-4-[4-(4-methylpiperazine-1-carbonyl)phenyl]-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-cyclohexyl-N-(dimethylsulfamoyl)-4-{4-[(morpholin-4-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-cyclohexyl-N-(dimethylsulfamoyl)-4-{4-[2-(morpholin-4-yl)ethyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-([1,4′-bipiperidin]-1′-yl)-3-cyclobutyl-N-(dimethylsulfamoyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-([1,4′-bipiperidin]-1′-yl)-3-cyclobutyl-N-(ethanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-([1,4′-bipiperidin]-1′-yl)-3-cyclobutyl-N-(cyclopropanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-(4-fluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-N-(oxolane-3-sulfonyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(methanesulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1-(2-methylpyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-(4-fluorophenyl)-N-(methanesulfonyl)-4-{4-[2-(morpholin-4-yl)ethyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-[methyl(propyl)sulfamoyl]-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    ethyl 4-[({3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carbonyl}sulfamoyl)amino]piperidine-1-carboxylate;
    3-cyclobutyl-N-(4-fluoropiperidine-1-sulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(1-methylcyclopropane-1-sulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(cyclopropanesulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(ethanesulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(2-methoxyethanesulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-{4-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]piperidine-1-sulfonyl}-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(dimethyl sulfamoyl)-1-(4-fluorophenyl)-4-{4-[1-(morpholin-4-yl)ethyl]piperidin-1-yl})-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-cyclohexyl-N-(methanesulfonyl)-4-{4-[(4-methylpiperazin-1-yl)methyl]phenyl)}-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-cyclohexyl-N-(dimethylsulfamoyl)-4-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-cyclohexyl-N-(dimethylsulfamoyl)-4-{4-[(piperidin-1-yl)methyl]phenyl)}-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-cyclohexyl-N-(dimethylsulfamoyl)-3-[(propan-2-yl)oxy]-4-{4-[(pyrrolidin-1-yl)methyl]phenyl})-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-(4-fluorophenyl)-N-(methanesulfonyl)-4-{4-[1-(morpholin-4-yl)ethyl]piperidin-1-yl})-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(ethanesulfonyl)-1-(4-fluorophenyl)-4-{4-[1-(morpholin-4-yl)ethyl]piperidin-1-yl})-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-(4-fluorophenyl)-N-(2-methoxyethanesulfonyl)-4-{4-[(morpholin-4-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-(4-fluorophenyl)-N-(2-hydroxyethanesulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(chloromethanesulfonyl)-3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-([1,4′-bipiperidin]-1′-yl)-3-cyclobutyl-1-(4-fluorophenyl)-N-(methanesulfonyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-([1,4′-bipiperidin]-1′-yl)-3-cyclobutyl-1-(4-fluorophenyl)-N-(oxolane-3-sulfonyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-(4-fluorophenyl)-4-{4-[2-(morpholin-4-yl)ethyl]piperidin-1-yl}-N-(oxolane-3-sulfonyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-([1,4′-bipiperidine]-1′-sulfonyl)-3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-([1,4′-bipiperidin]-1′-yl)-3-cyclobutyl-N-[3-(morpholin-4-yl)propane-1-sulfonyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(4-methylpiperazine-1-sulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(dimethyl sulfamoyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    ethyl 4-{[(3-cyclobutyl-1-phenyl-4-{4-[(pyrrolidin-1-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carbonyl)sulfamoyl]amino}piperidine-1-carboxylate;
    3-cyclobutyl-N-{4-[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]piperidine-1-sulfonyl}-1-phenyl-4-{4-[(pyrrolidin-1-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(4-fluoropiperidine-1-sulfonyl)-1-phenyl-4-{4-[(pyrrolidin-1-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(4-methylpiperazine-1-sulfonyl)-1-phenyl-4-{4-[(pyrrolidin-1-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(1-methylcyclopropane-1-sulfonyl)-1-phenyl-4-{4-[(pyrrolidin-1-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(cyclopropanesulfonyl)-1-phenyl-4-{4-[(pyrrolidin-1-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(ethanesulfonyl)-1-phenyl-4-{4-[(pyrrolidin-1-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(2-methoxyethanesulfonyl)-1-phenyl-4-{4-[(pyrrolidin-1-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(2-methylpropane-2-sulfonyl)-1-phenyl-4-{4-[(pyrrolidin-1-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(ethanesulfonyl)-1-(4-fluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-(cyclobutyloxy)-1-cyclohexyl-4-{4-[(morpholin-4-yl)methyl]phenyl}-N-(oxolane-3-sulfonyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-cyclohexyl-N-(oxolane-3-sulfonyl)-4-[4-(pyridin-4-yl)piperazin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-cyclohexyl-N-(dimethylsulfamoyl)-4-[4-(pyridin-4-yl)piperazin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-cyclohexyl-N-(ethanesulfonyl)-4-[4-(pyridin-4-yl)piperazin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-(4-fluorophenyl)-N-[(2-methoxyethyl)(methyl)sulfamoyl]-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-([1,4′-bipiperidin]-1′-yl)-3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(methanesulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1-[2-(oxan-4-yl)pyridin-4-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(methanesulfonyl)-1-(2-methoxypyridin-4-yl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-cyclohexyl-N-(dimethylsulfamoyl)-4-{4-[(morpholin-4-yl)methyl]phenyl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-cyclohexyl-N-(dimethylsulfamoyl)-4-{4-[2-(morpholin-4-yl)ethyl]phenyl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(but-3-yne-1-sulfonyl)-3-cyclobutyl-1-(4-fluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-([1,4′-bipiperidin]-1′-yl)-3-cyclobutyl-N-(ethanesulfonyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-{4-[(1R)-1-(morpholin-4-yl)ethyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(dimethyl sulfamoyl)-1-(4-fluorophenyl)-4-{4-[(1S)-1-(morpholin-4-yl)ethyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-(cyclobutyloxy)-1-cyclohexyl-N-(dimethyl sulfamoyl)-4-{4-[(morpholin-4-yl)methyl]phenyl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-(4-fluorophenyl)-N-[methyl(propan-2-yl)sulfamoyl]-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-[ethyl(methyl)sulfamoyl]-1-(4-fluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-(4-fluorophenyl)-N-(3-methoxyazetidine-1-sulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-(4-fluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-N-(pyrrolidine-1-sulfonyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-(4-fluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-N-(2,2,2-trifluoroethanesulfonyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-(4-fluorophenyl)-N-(morpholine-4-sulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-([1,4′-bipiperidin]-1′-yl)-3-cyclobutyl-1-(4-fluorophenyl)-N-(2-methoxyethanesulfonyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(dimethylsulfamoyl)-1-[2-(morpholin-4-yl)pyridin-4-yl]-4-[(oxan-4-yl)methoxy]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(methanesulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-[2-(oxan-4-yl)pyridin-4-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-(4-fluorophenyl)-N-(2-hydroxyethanesulfonyl)-4-{4-[2-(morpholin-4-yl)ethyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    methyl 4-(1-{3-cyclobutyl-6-[(dimethyl sulfamoyl)carbamoyl]-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridin-4-yl}piperidin-4-yl)piperazine-1-carboxylate;
    4-[4-(4-acetylpiperazin-1-yl)piperidin-1-yl]-3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(ethanesulfonyl)-1-(4-fluorophenyl)-4-{4-[(morpholin-4-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-(4-fluorophenyl)-4-{4-[(morpholin-4-yl)methyl]piperidin-1-yl}-N-(oxolane-3-sulfonyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    ethyl 4-[1-(4-fluorophenyl)-6-[(methanesulfonyl)carbamoyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl]piperidine-1-carboxylate;
    ethyl 4-{6-[(dimethylsulfamoyl)carbamoyl]-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl}piperidine-1-carboxylate;
    3-cyclobutyl-N-(dimethyl sulfamoyl)-1-(3-methylphenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(dimethylsulfamoyl)-1-(3-methoxyphenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(dimethylsulfamoyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-[4-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-[4-(ethoxymethyl)-4-fluoropiperidin-1-yl]-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-{4-fluoro-4-[(2-methoxyethoxy)methyl]piperidin-1-yl}-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-{3-fluoro-3-[(2-methoxyethoxy)methyl]piperidin-1-yl}-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-[4-fluoro-4-(methoxymethyl)piperidin-1-yl]-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(4-cyanopiperidine-1-sulfonyl)-3-cyclobutyl-1-(4-fluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-(4-fluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-N-(oxetane-3-sulfonyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(cyclopropanesulfonyl)-1-(4-fluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-(4-fluorophenyl)-N-(1-methylcyclopropane-1-sulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(methanesulfonyl)-1-(3-methylphenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(methanesulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-[4-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluoro-3-methylphenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(dimethylsulfamoyl)-1-(3-fluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(dimethyl sulfamoyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-(4-fluoro-3-methylphenyl)-N-(methanesulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-(3-fluorophenyl)-N-(methanesulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(methanesulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-(4-fluorophenyl)-N-(methylsulfamoyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-(4-fluorophenyl)-N-(methanesulfonyl)-4-[(4-methylpiperazin-1-yl)methyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-(4-fluorophenyl)-N-(methanesulfonyl)-4-[(morpholin-4-yl)methyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(dimethyl sulfamoyl)-1-(4-fluorophenyl)-4-[(morpholin-4-yl)methyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(dimethyl sulfamoyl)-1-(4-fluorophenyl)-4-{[4-(methoxymethyl)piperidin-1-yl]methyl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-(4-cyano[1,4′-bipiperidin]-1′-yl)-3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[4-(3-cyanoazetidin-1-yl)piperidin-1-yl]-3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-[4-(3-methoxypyrrolidin-1-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(dimethylsulfamoyl)-4-(4-fluoro[1,4′-bipiperidin]-1′-yl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-(4,4-difluoro[1,4′-bipiperidin]-1′-yl)-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[4-(2-cyanomorpholin-4-yl)piperidin-1-yl]-3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-{4-[methyl(oxan-4-yl)amino]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(dimethylsulfamoyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-{2-[(propan-2-yl)oxy]pyridin-4-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(methanesulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-{2-[(propan-2-yl)oxy]pyridin-4-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(dimethylsulfamoyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1-[2-(oxan-4-yl)pyridin-4-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-[4-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-[3-(morpholin-4-yl)-1-oxa-8-azaspiro[4.5]decan-8-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-cyclohexyl-N-(dimethylsulfamoyl)-3-[(propan-2-yl)oxy]-4-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-cyclohexyl-N-(dimethylsulfamoyl)-4-[4-(2-methylpyridin-4-yl)piperazin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-cyclohexyl-4-[6-(4-cyclopropylpiperazin-1-yl)pyridin-3-yl]-N-(dimethyl sulfamoyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-(4-fluorophenyl)-N-(3-fluoropyrrolidine-1-sulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-(4-fluorophenyl)-N-(3-methoxypyrrolidine-1-sulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-3-cyclobutyl-N-(dimethylsulfamoyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-(4-fluorophenyl)-N-[4-(methoxymethyl)piperidine-1-sulfonyl]-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(dimethyl sulfamoyl)-1-(4-fluorophenyl)-4-[4-(3-fluoropyrrolidin-1-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-cyclohexyl-N-(dimethylsulfamoyl)-4-{6-[4-(propan-2-yl)piperazin-1-yl]pyridin-3-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-cyclohexyl-N-(dimethylsulfamoyl)-4-{4-[1-(morpholin-4-yl)ethyl]phenyl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-cyclohexyl-4-{4-[4-(dimethylamino)piperidine-1-carbonyl]phenyl}-N-(methanesulfonyl)-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-cyclohexyl-4-{4-[4-(dimethylamino)piperidine-1-carbonyl]phenyl}-N-(2-methoxyethanesulfonyl)-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-cyclohexyl-4-{4-[4-(dimethylamino)piperidine-1-carbonyl]phenyl}-N-(dimethylsulfamoyl)-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-cyclohexyl-N-(dimethylsulfamoyl)-4-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-(4-fluorophenyl)-N-(methanesulfonyl)-4-(4-methoxy[1,4′-bipiperidin]-1′-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-[4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl]-N-(dimethylsulfamoyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(cyclopropanesulfonyl)-4-[4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-cyclohexyl-N-(dimethylsulfamoyl)-4-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-cyclohexyl-N-(dimethylsulfamoyl)-4-{6-[4-(2-methoxyethyl)piperazin-1-yl]pyridin-3-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-cyclohexyl-N-(dimethylsulfamoyl)-4-{4-[4-(propan-2-yl)piperazin-1-yl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-[4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl]-N-[methyl(propyl)sulfamoyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-[4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl]-N-(morpholine-4-sulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-[4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl]-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-[4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl]-N-(1-methylcyclopropane-1-sulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-[4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl]-N-(methylsulfamoyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-cyclohexyl-4-[4-(4-cyclopropylpiperazin-1-yl)phenyl]-N-(dimethylsulfamoyl)-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-{4-[3-(trifluoromethyl)pyrrolidin-1-yl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[4-(3-cyanopyrrolidin-1-yl)piperidin-1-yl]-3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-(3-cyano[1,4′-bipiperidin]-1′-yl)-3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(dimethylsulfamoyl)-4-(3-fluoro[1,4′-bipiperidin]-1′-yl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-(4-fluorophenyl)-N-(methanesulfonyl)-4-{4-[3-(trifluoromethyl)pyrrolidin-1-yl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[4-(3-cyanopyrrolidin-1-yl)piperidin-1-yl]-3-cyclobutyl-1-(4-fluorophenyl)-N-(methanesulfonyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-(3-cyano[1,4′-bipiperidin]-1′-yl)-3-cyclobutyl-1-(4-fluorophenyl)-N-(methanesulfonyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-(3-fluoro[1,4′-bipiperidin]-1′-yl)-1-(4-fluorophenyl)-N-(methanesulfonyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-(4-fluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-N-(piperidine-1-sulfonyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(3-fluoroazetidine-1-sulfonyl)-1-(4-fluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-[4-(3-methoxyazetidin-1-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-[3-(trifluoromethyl)[1,4′-bipiperidin]-1′-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-(3-methoxy[1,4′-bipiperidin]-1′-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-[4-(2,2-dimethylmorpholin-4-yl)piperidin-1-yl]-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(2-acetamidoethanesulfonyl)-3-cyclobutyl-1-(4-fluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-[2-(difluoromethoxy)pyridin-4-yl]-N-(dimethylsulfamoyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(azetidine-1-sulfonyl)-3-cyclobutyl-1-(4-fluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-(4-fluorophenyl)-N-[(2R)-2-(methoxymethyl)pyrrolidine-1-sulfonyl]-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-(4-fluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-N-[(oxan-4-yl)sulfamoyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-(4-fluorophenyl)-N-[methyl(oxan-4-yl)sulfamoyl]-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(3,3-difluoroazetidine-1-sulfonyl)-1-(4-fluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[(3S)-4-benzyl-3-methylpiperazin-1-yl]-3-cyclobutyl-1-cyclohexyl-N-(dimethyl sulfamoyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[(3R)-4-benzyl-3-methylpiperazin-1-yl]-3-cyclobutyl-1-cyclohexyl-N-(dimethyl sulfamoyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-[4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl]-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-(9-cyclopropyl-3,9-diazaspiro[5.5]undecan-3-yl)-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-(4-fluorophenyl)-N-(methanesulfonyl)-4-[4-(3-methoxyazetidin-1-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-(4-fluorophenyl)-N-(methanesulfonyl)-4-[3-(trifluoromethyl) [1,4′-bipiperidin]-1′-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-(4-fluorophenyl)-N-(methanesulfonyl)-4-(3-methoxy[1,4′-bipiperidin]-1′-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-[4-(2,2-dimethylmorpholin-4-yl)piperidin-1-yl]-1-(4-fluorophenyl)-N-(methanesulfonyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-{4-[(pyrrolidin-1-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    ethyl 4-(1-{3-cyclobutyl-6-[(dimethylsulfamoyl)carbamoyl]-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridin-4-yl}piperidin-4-yl)piperazine-1-carboxylate;
    3-cyclobutyl-N-(dimethyl sulfamoyl)-1-(4-fluorophenyl)-4-{4-[(2-methoxyethyl)(methyl)amino]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-(4-fluorophenyl)-N-(methoxysulfamoyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-[1-(4,4-difluorocyclohexyl)piperidin-4-yl]-1-(4-fluorophenyl)-N-(methanesulfonyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-[1-(4,4-difluorocyclohexyl)piperidin-4-yl]-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-{[4-(morpholin-4-yl)piperidin-1-yl]methyl})-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-(4-fluorophenyl)-N-(methanesulfonyl)-4-{[4-(morpholin-4-yl)piperidin-1-yl]methyl})-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-cyclohexyl-4-{4-[(4-cyclopropylpiperazin-1-yl)methyl]phenyl}-N-(methanesulfonyl)-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-[1-(propan-2-yl)piperidin-4-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-(4-fluorophenyl)-N-(methanesulfonyl)-4-[1-(oxan-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-(4-fluorophenyl)-N-(methanesulfonyl)-4-{1-[(oxan-4-yl)methyl]piperidin-4-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-{1-[(oxan-4-yl)methyl]piperidin-4-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-{1-[(2,5-dimethoxyoxolan-3-yl)methyl]piperidin-4-yl}-1-(4-fluorophenyl)-N-(methanesulfonyl)-1H-pyrazolo[3,4-b]pyridine-6-carb oxamide;
    3-cyclobutyl-1-(4-fluorophenyl)-N-(methanesulfonyl)-4-[1-(3,3,3-trifluoropropyl)piperidin-4-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-[1-(3,3,3-trifluoropropyl)piperidin-4-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-(4-hydroxy[1,4′-bipiperidin]-1′-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    methyl {3-cyclobutyl-1-(4-fluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carbonyl}sulfamate;
    3-cyclobutyl-N-(dimethyl sulfamoyl)-1-(4-fluorophenyl)-4-{4-[4-(2-methoxyethyl)piperazin-1-yl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-(4-fluorophenyl)-4-[4-(methoxymethyl)piperidin-1-yl]-N-[3-(morpholin-4-yl)pyrrolidine-1-sulfonyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(4-cyclopropylpiperazine-1-sulfonyl)-1-(4-fluorophenyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-(4-fluorophenyl)-N-[4-(2-methoxyethyl)piperazine-1-sulfonyl]-4-[4-(methoxymethyl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-(4-fluorophenyl)-N-(methanesulfonyl)-4-[1-(propan-2-yl)piperidin-4-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-[1-(oxan-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-[1-(cyclopropylmethyl)piperidin-4-yl]-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-[9-(oxetan-3-yl)-3,9-diazaspiro[5.5]undecan-3-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-{4-[4-(oxetan-3-yl)piperazin-1-yl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-[(1-cyclopropylpiperidin-4-yl)methoxy]-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-[(1-cyclobutylpiperidin-4-yl)methoxy]-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-[(1-cyclohexylpiperidin-4-yl)methoxy]-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-{[1-(oxan-4-yl)piperidin-4-yl]methoxy}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-{1-[(2,5-dimethoxyoxolan-3-yl)methyl]piperidin-4-yl}-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(dimethylsulfamoyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-{2-[(propan-2-yl)oxy]pyrimidin-4-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(dimethylsulfamoyl)-1-(2-ethoxypyrimidin-4-yl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)-N-(dimethylsulfamoyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-(4-fluorophenyl)-N-(4-methylpiperazine-1-sulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(dimethyl sulfamoyl)-1-(4-fluorophenyl)-4-[1-(propan-2-yl)octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-(1-cyclobutyloctahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-[1-(oxetan-3-yl)octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-[1-(oxan-4-yl)octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-(4-fluorophenyl)-4-(4-methoxy[1,4′-bipiperidin]-1′-yl)-N-(methyl sulfamoyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-(4-fluorophenyl)-4-(4-methoxy[1,4′-bipiperidin]-1′-yl)-N-sulfamoyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-cyclohexyl-4-[4-(hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carbonyl)phenyl]-N-(methanesulfonyl)-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(azetidine-1-sulfonyl)-3-cyclobutyl-1-(4-fluorophenyl)-4-(4-methoxy[1,4′-bipiperidin]-1′-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-cyclohexyl-4-(4-{[3-(dimethylamino)azetidin-1-yl]methyl}phenyl)-N-(methanesulfonyl)-3-[(propan-2-yl)oxy]-1H-pyrazzolo[3,4-b]pyridine-6-carboxamide;
    1-cyclohexyl-N-(methanesulfonyl)-3-[(propan-2-yl)oxy]-4-(4-{[4-(propan-2-yl)piperazin-1-yl]methyl}phenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-cyclohexyl-N-(methanesulfonyl)-4-{4-[(4-methoxypiperidin-1-yl)methyl]phenyl}-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-cyclohexyl-N-(methanesulfonyl)-4-{4-[(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methyl]phenyl}-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-cyclohexyl-N-(methanesulfonyl)-4-[4-(5-methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carbonyl)phenyl]-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-(4-fluorophenyl)-N-(methylsulfamoyl)-4-{4-[4-(propan-2-yl)piperazin-1-yl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    4-[4-(4-cyano-1-methylpiperidin-4-yl)phenyl]-1-cyclohexyl-N-(methanesulfonyl)-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-cyclohexyl-4-{4-[3-(dimethylamino)azetidine-1-carbonyl]phenyl}-N-(methanesulfonyl)-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-cyclohexyl-N-(methanesulfonyl)-4-{4-[(8-methyl-2-oxa-5, 8-diazaspiro[3.5]nonan-5-yl)methyl]phenyl}-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-cyclohexyl-4-{4-[(4-ethylpiperazin-1-yl)methyl]phenyl}-N-(methanesulfonyl)-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    1-cyclohexyl-4-(4-{[4-(dimethylamino)piperidin-1-yl]methyl}phenyl)-N-(methanesulfonyl)-3-[(propan-2-yl)oxy]-1H-pyrazzolo[3,4-b]pyridine-6-carboxamide;
    1-(4-fluorophenyl)-N-(methanesulfonyl)-4-(4-methoxy[1,4′-bipiperidin]-1′-yl)-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-(4-fluorophenyl)-N-(3-methoxyazetidine-1-sulfonyl)-4-(4-methoxy[1,4′-bipiperidin]-1′-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(3-fluoroazetidine-1-sulfonyl)-1-(4-fluorophenyl)-4-(4-methoxy[1,4′-bipiperidin]-1′-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-(4-fluorophenyl)-4-(4-methoxy[1,4′-bipiperidin]-1′-yl)-N-(morpholine-4-sulfonyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(methanesulfonyl)-4-[4-(morpholin-4-yl)cyclohexyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(dimethylsulfamoyl)-4-[4-(morpholin-4-yl)cyclohexyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-4-(4-fluoro[1,4′-bipiperidin]-1′-yl)-1-(4-fluorophenyl)-N-(methyl sulfamoyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    N-(azetidine-1-sulfonyl)-3-cyclobutyl-1-(4-fluorophenyl)-4-{4-[4-(propan-2-yl)piperazin-1-yl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-[3-(difluoromethoxy)phenyl]-N-(dimethylsulfamoyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-(4-fluorophenyl)-N-(methanesulfonyl)-N-methyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(methanesulfonyl)-N-methyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(methanesulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-N-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(ethanesulfonyl)-N-methyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-N-(ethanesulfonyl)-N-methyl-1-phenyl-4-{4-[(pyrrolidin-1-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    2-(3-cyclobutyl-1-phenyl-4-{4-[(pyrrolidin-1-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carbonyl)-6-methyl-1λ6,2,6-thiadiazinane-1,1-dione;
    2-(3-cyclobutyl-1-phenyl-4-{4-[(pyrrolidin-1-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carbonyl)-1λ6,2-thiazolidine-1,1-dione;
    3-cyclobutyl-N-(methanesulfonyl)-N-methyl-1-phenyl-4-{4-[(pyrrolidin-1-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    2-(3-cyclobutyl-1-phenyl-4-{4-[(pyrrolidin-1-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carbonyl)-1λ6,2-thiazinane-1,1-dione;
    2-{3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carbonyl}-6-methyl-1λ6,2,6-thiadiazinane-1,1-dione;
    2-{3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carbonyl}-1λ6,2-thiazolidine-1,1-dione;
    2-{3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carbonyl}-1λ6,2-thiazinane-1,1-dione;
    2-{3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carbonyl}-1λ6,2-thiazolidine-1,1-dione;
    2-{3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carbonyl}-1λ6,2-thiazinane-1,1-dione;
    3-cyclobutyl-1-(4-fluorophenyl)-4-[4-(methoxymethyl)piperidin-1-yl]-N-(methylsulfamoyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-(4-fluorophenyl)-N-(2-methoxyethanesulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-(4-fluorophenyl)-4-[4-(methoxymethyl)piperidin-1-yl]-N-(morpholine-4-sulfonyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-(4-fluorophenyl)-N-(3-hydroxypropane-1-sulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    ethyl 4-[({3-cyclobutyl-1-(4-fluorophenyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carbonyl}sulfamoyl)amino]piperidine-1-carboxylate;
    3-cyclobutyl-1-(4-fluorophenyl)-4-[4-(methoxymethyl)piperidin-1-yl]-N-[(oxetan-3-yl)sulfamoyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-(4-fluorophenyl)-4-[4-(methoxymethyl)piperidin-1-yl]-N-[(oxan-4-yl)sulfamoyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    3-cyclobutyl-1-(4-fluorophenyl)-4-[4-(methoxymethyl)piperidin-1-yl]-N-[4-(morpholin-4-yl)piperidine-1-sulfonyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
    ethyl 4-{3-cyclobutyl-1-(4-fluorophenyl)-6-[(2-methoxyethanesulfonyl)carbamoyl]-1H-pyrazolo[3,4-b]pyridin-4-yl}piperazine-1-carboxylate;
    ethyl 4-{3-cyclobutyl-1-(4-fluorophenyl)-6-[(morpholine-4-sulfonyl)carbamoyl]-1H-pyrazolo[3,4-b]pyridin-4-yl}piperazine-1-carboxylate;
    ethyl 4-{3-cyclobutyl-1-(4-fluorophenyl)-6-[(methanesulfonyl)carbamoyl]-1H-pyrazolo[3,4-b]pyridin-4-yl}piperazine-1-carboxylate;
    ethyl 4-{3-cyclobutyl-1-(4-fluorophenyl)-6-[(methylsulfamoyl)carbamoyl]-1H-pyrazolo[3,4-b]pyridin-4-yl}piperazine-1-carboxylate;
    2-methylpropyl 4-{3-cyclobutyl-1-(4-fluorophenyl)-6-[(methanesulfonyl)carbamoyl]-1H-pyrazolo[3,4-b]pyridin-4-yl}piperazine-1-carboxylate;
    2-methylpropyl 4-{3-cyclobutyl-1-(4-fluorophenyl)-6-[(morpholine-4-sulfonyl)carbamoyl]-1H-pyrazolo[3,4-b]pyridin-4-yl}piperazine-1-carboxylate;
    2-methylpropyl 4-{3-cyclobutyl-1-(4-fluorophenyl)-6-[(2-methoxyethanesulfonyl)carbamoyl]-1H-pyrazolo[3,4-b]pyridin-4-yl}piperazine-1-carboxylate;
    2-methylpropyl 4-{3-cyclobutyl-1-(4-fluorophenyl)-6-[(methylsulfamoyl)carbamoyl]-1H-pyrazolo[3,4-b]pyridin-4-yl}piperazine-1-carboxylate;
    3-cyclobutyl-1-(4-fluorophenyl)-4-(9-methyl-3,9-diazaspiro[5.5]undecan-3-yl)-N-(morpholine-4-sulfonyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide; and
    N-(2-aminopyridine-3-sulfonyl)-3-cyclobutyl-1-(4-fluorophenyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide.


Compounds of the invention are named by using Name 2015 naming algorithm by Advanced Chemical Development, Struct=Name naming algorithm as part of CHEMDRAW® ULTRA v. 12.0.2.1076, or Accelrys Draw 4.2.
Compounds of the invention may exist as stereoisomers wherein asymmetric or chiral centers are present. These stereoisomers are “R” or “S” depending on the configuration of substituents around the chiral carbon atom. The terms “R” and “S” used herein are configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, in Pure Appl. Chem., 1976, 45: 13-30. The invention contemplates various stereoisomers and mixtures thereof and these are specifically included within the scope of this invention. Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or diastereomers. Individual stereoisomers of compounds of the invention may be prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by methods of resolution well-known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and optional liberation of the optically pure product from the auxiliary as described in Furniss, Hannaford, Smith, and Tatchell, “Vogel's Textbook of Practical Organic Chemistry”, 5th edition (1989), Longman Scientific & Technical, Essex CM20 2JE, England, or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns or (3) fractional recrystallization methods.
Compounds of the invention may exist as cis or trans isomers, wherein substituents on a ring may attached in such a manner that they are on the same side of the ring (cis) relative to each other, or on opposite sides of the ring relative to each other (trans). For example, cyclobutane may be present in the cis or trans configuration, and may be present as a single isomer or a mixture of the cis and trans isomers. Individual cis or trans isomers of compounds of the invention may be prepared synthetically from commercially available starting materials using selective organic transformations, or prepared in single isomeric form by purification of mixtures of the cis and trans isomers. Such methods are well-known to those of ordinary skill in the art, and may include separation of isomers by recrystallization or chromatography.
It should be understood that the compounds of the invention may possess tautomeric forms, as well as geometric isomers, and that these also constitute an aspect of the invention.
The present disclosure includes all pharmaceutically acceptable isotopically-labelled compounds of formula (I) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature. Examples of isotopes suitable for inclusion in the compounds of the disclosure include isotopes of hydrogen, such as 2H and 3H, carbon, such as 11C, 13C and 14C, chlorine, such as 36Cl, fluorine, such as 18F, iodine, such as 123I and 125I, nitrogen, such as 13N and 15N, oxygen, such as 15O, 17O and 18O, phosphorus, such as 32P, and sulphur, such as 35S. Certain isotopically-labelled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. 3H, and carbon-14, i.e. 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes such as deuterium, i.e. 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Substitution with positron emitting isotopes, such as 11C, 18F, 15O and 13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds of formula (I) may generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed.
Thus, the formula drawings within this specification can represent only one of the possible tautomeric, geometric, or stereoisomeric forms. It is to be understood that the invention encompasses any tautomeric, geometric, or stereoisomeric form, and mixtures thereof, and is not to be limited merely to any one tautomeric, geometric, or stereoisomeric form utilized within the formula drawings.
Compounds of formula (I) may be used in the form of pharmaceutically acceptable salts. The phrase “pharmaceutically acceptable salt” means those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio.
Pharmaceutically acceptable salts have been described in S. M. Berge et al. J. Pharmaceutical Sciences, 1977, 66: 1-19.
Compounds of formula (I) may contain either a basic or an acidic functionality, or both, and can be converted to a pharmaceutically acceptable salt, when desired, by using a suitable acid or base. The salts may be prepared in situ during the final isolation and purification of the compounds of the invention.
Examples of acid addition salts include, but are not limited to acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isothionate), lactate, malate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Also, the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides such as, but not limited to, methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as, but not limited to, decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkyl halides like benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained. Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid and such organic acids as acetic acid, fumaric acid, maleic acid, 4-methylbenzenesulfonic acid, succinic acid, and citric acid.
Basic addition salts may be prepared in situ during the final isolation and purification of compounds of this invention by reacting a carboxylic acid-containing moiety with a suitable base such as, but not limited to, the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, cations based on alkali metals or alkaline earth metals such as, but not limited to, lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like and nontoxic quaternary ammonia and amine cations including ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine and the like. Other examples of organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine and the like.
The term “pharmaceutically acceptable prodrug” or “prodrug” as used herein refers to derivatives of the compounds of the invention which have cleavable groups. Such derivatives become, by solvolysis or under physiological conditions, the compounds of the invention which are pharmaceutically active in vivo. Prodrugs of the compounds of the invention are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use.
The invention contemplates compounds of formula (I) formed by synthetic means or formed by in vivo biotransformation of a prodrug.
Compounds described herein may exist in unsolvated as well as solvated forms, including hydrated forms, such as hemi-hydrates. In general, the solvated forms, with pharmaceutically acceptable solvents such as water and ethanol among others are equivalent to the unsolvated forms for the purposes of the invention.
Pharmaceutical Compositions
When employed as a pharmaceutical, a compound of the invention is typically administered in the form of a pharmaceutical composition. Such compositions can be prepared in a manner well known in the pharmaceutical art and comprise a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier. The phrase “pharmaceutical composition” refers to a composition suitable for administration in medical or veterinary use.
The pharmaceutical compositions that comprise a compound of formula (I), alone or in combination with further therapeutically active ingredient, may be administered to the subjects orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments or drops), bucally or as an oral or nasal spray. The term “parenterally” as used herein, refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.
The term “pharmaceutically acceptable carrier” as used herein, means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which may serve as pharmaceutically acceptable carriers are sugars such as, but not limited to, lactose, glucose and sucrose; starches such as, but not limited to, corn starch and potato starch; cellulose and its derivatives such as, but not limited to, sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as, but not limited to, cocoa butter and suppository waxes; oils such as, but not limited to, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols; such a propylene glycol; esters such as, but not limited to, ethyl oleate and ethyl laurate; agar; buffering agents such as, but not limited to, magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as, but not limited to, sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants may also be present in the composition, according to the judgment of the formulator.
Pharmaceutical compositions for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous diluents, solvents, or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), vegetable oils (such as olive oil), injectable organic esters (such as ethyl oleate), and suitable mixtures thereof. Proper fluidity may be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption, such as aluminum monostearate and gelatin.
In some cases, in order to prolong the effect of the drug, it may be desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally-administered drug form may be accomplished by dissolving or suspending the drug in an oil vehicle.
Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release may be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
The injectable formulations may be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In certain embodiments, solid dosage forms may contain from 1% to 95% (w/w) of a compound of formula (I). In certain embodiments, the compound of formula (I), or pharmaceutically acceptable salts thereof, may be present in the solid dosage form in a range of from 5% to 70% (w/w). In such solid dosage forms, the active compound may be mixed with at least one inert, pharmaceutically acceptable carrier, such as sodium citrate or dicalcium phosphate and/or a), fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
The pharmaceutical composition may be a unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampules. Also, the unit dosage form may be a capsule, tablet, cachet, or lozenge itself, or it may be the appropriate number of any of these in packaged form. The quantity of active component in a unit dose preparation may be varied or adjusted from 0.1 mg to 1000 mg, from 1 mg to 100 mg, or from 1% to 95% (w/w) of a unit dose, according to the particular application and the potency of the active component. The composition may, if desired, also contain other compatible therapeutic agents.
The dose to be administered to a subject may be determined by the efficacy of the particular compound employed and the condition of the subject, as well as the body weight or surface area of the subject to be treated. The size of the dose also will be determined by the existence, nature, and extent of any adverse side-effects that accompany the administration of a particular compound in a particular subject. In determining the effective amount of the compound to be administered in the treatment or prophylaxis of the disorder being treated, the physician may evaluate factors such as the circulating plasma levels of the compound, compound toxicities, and/or the progression of the disease, etc.
For administration, compounds may be administered at a rate determined by factors that may include, but are not limited to, the LD50 of the compound, the pharmacokinetic profile of the compound, contraindicated drugs, and the side-effects of the compound at various concentrations, as applied to the mass and overall health of the subject. Administration may be accomplished via single or divided doses.
The compounds utilized in the pharmaceutical method of the invention may be administered at the initial dosage of about 0.001 mg/kg to about 100 mg/kg daily. In certain embodiments, the daily dose range is from about 0.1 mg/kg to about 10 mg/kg. The dosages, however, may be varied depending upon the requirements of the subject, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Treatment may be initiated with smaller dosages, which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired.
Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such carriers as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coatings well-known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also be of a composition such that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
The active compounds may also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned carriers.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, and fatty acid esters of sorbitan and mixtures thereof.
Besides inert diluents, the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents. Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth and mixtures thereof.
Compositions for rectal or vaginal administration are preferably suppositories which may be prepared by mixing the compounds with suitable non-irritating carriers or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
Compounds may also be administered in the form of liposomes. Liposomes generally may be derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals which are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes may be used. The present compositions in liposome form may contain, in addition to a compound of the invention, stabilizers, preservatives, excipients, and the like. Examples of lipids include, but are not limited to, natural and synthetic phospholipids, and phosphatidyl cholines (lecithins), used separately or together.
Methods to form liposomes have been described, see example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq. Dosage forms for topical administration of a compound described herein include powders, sprays, ointments, and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers or propellants which may be required. Opthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
A compound of the invention may also be administered in sustained release forms or from sustained release drug delivery systems.
Methods of Use
The compounds and compositions using any amount and any route of administration may be administered to a subject for the treatment or prevention of cystic fibrosis, pancreatic insufficiency, Sjögren's Syndrome (SS), chronic obstructive lung disease (COLD), or chronic obstructive airway disease (COAD).
The term “administering” refers to the method of contacting a compound with a subject. Thus, the compounds may be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, parentally, or intraperitoneally. Also, the compounds described herein may be administered by inhalation, for example, intranasally. Additionally, the compounds may be administered transdermally, topically, and via implantation. In certain embodiments, the compounds and compositions thereof may be delivered orally. The compounds may also be delivered rectally, bucally, intravaginally, ocularly, or by insufflation. CFTR-modulated disorders and conditions may be treated prophylactically, acutely, and chronically using compounds and compositions thereof, depending on the nature of the disorder or condition. Typically, the host or subject in each of these methods is human, although other mammals may also benefit from the administration of compounds and compositions thereof as set forth hereinabove.
Compounds of the invention are useful as modulators of CFTR. Thus, the compounds and compositions are particularly useful for treating or lessening the severity or progression of a disease, disorder, or a condition where hyperactivity or inactivity of CFTR is involved. Accordingly, the invention provides a method for treating cystic fibrosis, pancreatic insufficiency, Sjögren's Syndrome (SS), chronic obstructive lung disease (COLD), or chronic obstructive airway disease (COAD) in a subject, wherein the method comprises the step of administering to said subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a preferred embodiment thereof as set forth above, with or without a pharmaceutically acceptable carrier. Particularly, the method is for the treatment or prevention of cystic fibrosis. In a more particular embodiment, the cystic fibrosis is caused by a Class I, II, III, IV, V, and/or VI mutation.
One embodiment is directed to a compound of the invention or a pharmaceutically acceptable salt thereof, or pharmaceutical compositions comprising a compound of the invention for use in medicine. One embodiment is directed to a compound of the invention or a pharmaceutically acceptable salt thereof, or pharmaceutical compositions thereof, for use in the treatment of cystic fibrosis, pancreatic insufficiency, Sjögren's Syndrome (SS), chronic obstructive lung disease (COLD) or chronic obstructive airway disease (COAD). In a more particular embodiment, the present invention provides compounds of the invention or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, for use in the treatment of cystic fibrosis. In a more particular embodiment, the cystic fibrosis is caused by a Class I, II, III, IV, V, and/or VI mutation.
One embodiment is directed to the use of a compound according to formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament. The medicament optionally can comprise one or more additional therapeutic agents. In some embodiments, the medicament is for use in the treatment of cystic fibrosis, pancreatic insufficiency, Sjögren's Syndrome (SS), chronic obstructive lung disease (COLD) or chronic obstructive airway disease (COAD). In a particular embodiment, the medicament is for use in the treatment of cystic fibrosis. In a more particular embodiment, the cystic fibrosis is caused by a Class I, II, III, IV, V, and/or VI mutation.
This invention also is directed to the use of a compound according to formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of cystic fibrosis, Sjögren's syndrome, pancreatic insufficiency, chronic obstructive lung disease, and chronic obstructive airway disease. The medicament optionally can comprise one or more additional therapeutic agents. In a particular embodiment, the invention is directed to the use of a compound according to formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of cystic fibrosis. In a more particular embodiment, the cystic fibrosis is caused by a Class I, II, III, IV, V, and/or VI mutation.
In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents. In a particular embodiment, the other therapeutic agent is a cystic fibrosis treatment agent. In a more particular embodiment, the cystic fibrosis is caused by a Class I, II, III, IV, V, and/or VI mutation.
The present compounds or pharmaceutically acceptable salts thereof may be administered as the sole active agent or it may be co-administered with other therapeutic agents, including other compounds or pharmaceutically acceptable salts thereof that demonstrate the same or a similar therapeutic activity and that are determined to be safe and efficacious for such combined administration. The present compounds may be co-administered to a subject. The term “co-administered” means the administration of two or more different therapeutic agents to a subject in a single pharmaceutical composition or in separate pharmaceutical compositions. Thus co-administration involves administration at the same time of a single pharmaceutical composition comprising two or more therapeutic agents or administration of two or more different compositions to the same subject at the same or different times.
The compounds of the invention or a pharmaceutically acceptable salt thereof may be co-administered with a therapeutically effective amount of one or more additional therapeutic agents to treat a CFTR mediated disease, where examples of the therapeutic agents include, but are not limited to antibiotics (for example, aminoglycosides, colistin, aztreonam, ciprofloxacin, and azithromycin), expectorants (for example, hypertonic saline, acetylcysteine, dornase alfa, and denufosol), pancreatic enzyme supplements (for example, pancreatin, and pancrelipase), epithelial sodium channel blocker (ENaC) inhibitors, CFTR modulators (for example, CFTR potentiators, CFTR correctors), and CFTR amplifiers. In one embodiment, the CFTR mediated disease is cystic fibrosis, chronic obstructive pulmonary disease (COPD), dry eye disease, pancreatic insufficiency, or Sjogren's syndrome. In one embodiment, the CFTR mediated disease is cystic fibrosis. In one embodiment, the compounds of the invention or pharmaceutically acceptable salts thereof may be co-administered with one or two CFTR modulators and one CFTR amplifier. In one embodiment, the compounds of the invention or pharmaceutically acceptable salts thereof may be co-administered with one potentiator, one or more correctors, and one CFTR amplifier. In one embodiment, the compounds of the invention or pharmaceutically acceptable salts thereof may be co-administered with one or more CFTR modulators. In one embodiment, the compounds of the invention or pharmaceutically acceptable salts thereof may be co-administered with one CFTR modulators. In one embodiment, the compounds of the invention or pharmaceutically acceptable salts thereof may be co-administered with two CFTR modulators. In one embodiment, the compounds of the invention or pharmaceutically acceptable salts thereof may be co-administered with three CFTR modulators. In one embodiment, the compounds of the invention or pharmaceutically acceptable salts thereof may be co-administered with one potentiator and one or more correctors. In one embodiment, the compounds of the invention or pharmaceutically acceptable salts thereof may be co-administered with one potentiator and one corrector. In one embodiment, the compounds of the invention or pharmaceutically acceptable salts thereof may be co-administered with one potentiator and two correctors. In one embodiment, the compounds of the invention or pharmaceutically acceptable salts thereof may be co-administered with one potentiator. In one embodiment, the compounds of the invention or pharmaceutically acceptable salts thereof may be co-administered with one or more correctors. In one embodiment, the compounds of the invention or pharmaceutically acceptable salts thereof may be co-administered with one corrector. In one embodiment, the compounds of the invention or pharmaceutically acceptable salts thereof may be co-administered with two correctors.
Examples of CFTR potentiators include, but are not limited to, Ivacaftor (VX-770), CTP-656, NVS-QBW251, FD1860293, PTI-808, GLPG2451, GLPG1837, N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-1H-pyrazole-5-carboxamide and 3-amino-N-[(2S)-2-hydroxypropyl]-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridine-2-carboxamide. Examples of potentiators are also disclosed in publications: WO2005120497, WO2008147952, WO2009076593, WO2010048573, WO2006002421, WO2011072241, WO2011113894, WO2013038373, WO2013038378, WO2013038381, WO2013038386, WO2013038390, WO2014180562, WO2015018823; and U.S. application Ser. Nos. 14/271,080, 14/451,619, and 15/164,317.
In one embodiment, the potentiator can be selected from the group consisting of:
Ivacaftor (VX-770, N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide);
CTP-656;
NVS-QBW251;
FD1860293;
PTI-808;
GLPG1837;
GLPG2451;

    2-(2-fluorobenzamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide;
    N-(3-carbamoyl-5,5,7,7-tetramethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl)-1H-pyrazole-5-carboxamide;
    2-(2-hydroxybenzamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide;
    2-(1-hydroxycyclopropanecarboxamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide;
    5,5,7,7-tetramethyl-2-(2-(trifluoromethyl)benzamido)-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide;
    2-(2-hydroxy-2-methylpropanamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide;
    2-(1-(hydroxymethyl)cyclopropanecarboxamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide;
    2-(3-hydroxy-2,2-dimethylpropanamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide;
    N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-5-methyl-1H-pyrazole-3-carboxamide;
    N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-5-cyclopropyl-1H-pyrazole-3-carboxamide;
    N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-5-isopropyl-1H-pyrazole-3-carboxamide;
    N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxamide;
    5-tert-butyl-N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-1H-pyrazole-3-carboxamide;
    N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-5-ethyl-1H-pyrazole-3-carboxamide;
    N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-3-ethyl-4-methyl-1H-pyrazole-5-carboxamide;
    2-(2-hydroxypropanamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide;
    N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-4-chloro-1H-pyrazole-3-carboxamide;
    N-(3-carbamoyl-5, 5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-1,4,6,7-tetrahydropyrano[4,3-c]pyrazole-3-carboxamide;
    4-bromo-N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-1H-pyrazole-3-carboxamide;
    N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-4-chloro-5-methyl-1H-pyrazole-3-carboxamide;
    N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-4-methyl-1H-pyrazole-3-carboxamide;
    2-(2-hydroxy-3,3-dimethylbutanamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide;
    2-[(2-hydroxy-4-methyl-pentanoyl)amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide;
    5-(2-methoxy-ethoxy)-1H-pyrazole-3-carboxylic acid (3-carbamoyl-5,5,7,7-tetramethyl-4, 7-dihydro-5H-thieno[2,3-c]pyran-2-yl)-amide;
    N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-4-(3-methoxypropyl)-1H-pyrazole-3-carboxamide;
    N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-4-(2-ethoxyethyl)-1H-pyrazole-3-carboxamide;
    2-[[(2S)-2-hydroxy-3,3-dimethyl-butanoyl]amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide;
    2-[[(2R)-2-hydroxy-3,3-dimethyl-butanoyl]amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide;
    2-[(2-hydroxy-2,3,3-trimethyl-butanoyl)amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide;
    [5-[(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)carbamoyl]pyrazol-1-yl]methyl dihydrogen phosphate;
    [3-[(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)carbamoyl]pyrazol-1-yl]methyl dihydrogen phosphate;
    N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-4-(1,4-dioxan-2-yl)-1H-pyrazole-3-carboxamide;
    5,5,7,7-tetramethyl-2-[[(2S)-3,3,3-trifluoro-2-hydroxy-2-methyl-propanoyl]amino]-4H-thieno[2,3-c]pyran-3-carboxamide;
    2-[[(2S)-2-hydroxypropanoyl]amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide;
    3-amino-N-(2-hydroxy-2-methylpropyl)-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridine-2-carboxamide;
    3-amino-N-[(4-hydroxy-1-methylpiperidin-4-yl)methyl]-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridine-2-carboxamide;
    3-amino-N-(3-hydroxy-2,2-dimethylpropyl)-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridine-2-carboxamide;
    3-amino-5-[(4-fluorophenyl)sulfonyl]-N-[(1-hydroxycyclopropyl)methyl]pyridine-2-carboxamide;
    3-amino-5-[(4-fluorophenyl)sulfonyl]-N-[(2R)-3,3,3-trifluoro-2-hydroxypropyl]pyridine-2-carboxamide;
    3-amino-5-[(3-fluorophenyl)sulfonyl]-N-(2-hydroxy-2-methylpropyl)pyridine-2-carboxamide;
    3-amino-N-[2-(cyclopropylamino)-2-oxoethyl]-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridine-2-carboxamide;
    (3-amino-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridin-2-yl)(azetidin-1-yl)methanone;
    (3-amino-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridin-2-yl)[3-(hydroxymethyl)azetidin-1-yl]methanone;
    (3-amino-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridin-2-yl)(3-fluoroazetidin-1-yl)methanone;
    3-amino-N-[(2R)-2-hydroxy-3-methoxypropyl]-5-{[4-(trifluoromethyl)phenyl]sulfonyl}pyridine-2-carboxamide;
    (3-amino-5-{[2-fluoro-4-(trifluoromethoxy)phenyl]sulfonyl}pyridin-2-yl)(3-hydroxyazetidin-1-yl)methanone;
    (3-amino-5-{[2-(trifluoromethoxy)phenyl]sulfonyl}pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methanone;
    rac-3-amino-N-[(3R,4S)-4-hydroxytetrahydro-2H-pyran-3-yl]-5-{[2-(trifluoromethoxy)phenyl]sulfonyl}pyridine-2-carboxamide;
    3-amino-5-[(4,4-difluoropiperidin-1-yl)sulfonyl]-N-(3,3,3-trifluoro-2-hydroxypropyl)pyridine-2-carboxamide;
    (3-amino-5-{[2-(trifluoromethoxy)phenyl]sulfonyl}pyridin-2-yl)[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]methanone;
    3-amino-N-(2-hydroxy-4-methylpentyl)-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridine-2-carboxamide;
    (3-amino-5-{[4-(trifluoromethyl)phenyl]sulfonyl}pyridin-2-yl)(3-hydroxy-3-methylazetidin-1-yl)methanone;
    3-amino-N-(3,3,3-trifluoro-2-hydroxypropyl)-5-{[4-(trifluoromethyl)piperidin-1-yl]sulfonyl}pyridine-2-carboxamide;
    3-amino-N-[2-hydroxy-1-(4-methoxyphenyl)ethyl]-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridine-2-carboxamide;
    3-amino-5-[(3,3-difluoroazetidin-1-yl)sulfonyl]-N-(3,3,3-trifluoro-2-hydroxypropyl)pyridine-2-carboxamide;
    3-amino-5-{[2-fluoro-4-(trifluoromethyl)phenyl]sulfonyl}-N-[(2S)-2-hydroxypropyl]pyridine-2-carboxamide;
    3-amino-5-{[2-fluoro-4-(trifluoromethyl)phenyl]sulfonyl}-N-[(2R)-2-hydroxy-3-methoxypropyl]pyridine-2-carboxamide;
    3-amino-N-[2-oxo-2-(propan-2-ylamino)ethyl]-5-{[4-(trifluoromethyl)phenyl]sulfonyl}pyridine-2-carboxamide;
    (3-amino-5-{[4-(trifluoromethyl)phenyl]sulfonyl}pyridin-2-yl)[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]methanone;
    3-amino-5-{[2-fluoro-4-(trifluoromethyl)phenyl]sulfonyl}-N-[(3R)-tetrahydrofuran-3-ylmethyl]pyridine-2-carboxamide;
    (3-amino-5-{[2-fluoro-4-(trifluoromethyl)phenyl]sulfonyl}pyridin-2-yl)[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]methanone;
    3-amino-5-{[2-fluoro-4-(trifluoromethyl)phenyl]sulfonyl}-N-[(3S)-tetrahydrofuran-3-ylmethyl]pyridine-2-carboxamide;
    3-amino-5-{[2-fluoro-4-(trifluoromethoxy)phenyl]sulfonyl}-N-[(3S)-tetrahydrofuran-3-ylmethyl]pyridine-2-carboxamide;
    3-amino-N-[2-hydroxy-3-(2,2,2-trifluoroethoxy)propyl]-5-{[4-(trifluoromethyl)phenyl]sulfonyl}pyridine-2-carboxamide;
    3-amino-N-(3-tert-butoxy-2-hydroxypropyl)-5-{[2-fluoro-4-(trifluoromethyl)phenyl]sulfonyl}pyridine-2-carboxamide;
    [3-amino-5-(phenylsulfonyl)pyridin-2-yl][3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]methanone;
    {3-amino-5-[(3-fluorophenyl)sulfonyl]pyridin-2-yl}[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]methanone; and
    3-amino-N-[(2S)-2-hydroxypropyl]-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridine-2-carboxamide.


Non-limiting examples of correctors include Lumacaftor (VX-809), 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-{1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)}cyclopropanecarboxamide (VX-661), VX-983, GLPG2222, GLPG2665, GLPG2851, VX-152, VX-440, FDL169, FDL304, FD2052160, FD2035659 and PTI-801. Examples of correctors are also disclosed in U.S. application Ser. Nos. 14/925,649, 14/926,727, 15/205,512, and 62/239,475.
In one embodiment, the corrector(s) can be selected from the group consisting of:

    Lumacaftor (VX-809);
    1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-{1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl}cyclopropanecarboxamide (VX-661);
    PTI-801;
    VX-983;
    GLPG2665;
    VX-152;
    VX-440;
    FDL169;
    FDL304;
    FD2052160;
    FD2035659;
    3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoic acid;
    3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]benzoic acid;
    3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-methyl-3,4-dihydro-2H-chromen-2-yl]benzoic acid;
    3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methyl-3,4-dihydro-2H-chromen-2-yl]benzoic acid;
    3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoic acid;
    3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]cyclohexanecarboxylic acid;
    3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic acid;
    3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]cyclohexanecarboxylic acid;
    3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-fluoro-3,4-dihydro-2H-chromen-2-yl]benzoic acid;
    3-({3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methyl-3,4-dihydro-2H-chromen-2-yl]benzoyl}amino)-1-methylcyclopentanecarboxylic acid;
    3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methyl-3,4-dihydro-2H-chromen-2-yl]-N-[(2R)-2,3-dihydroxypropyl]benzamide;
    3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-(2-methoxyethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic acid;
    3-[(2R,4R)-7-(benzyloxy)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]benzoic acid;
    3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-(2-fluoroethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic acid;
    3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-(trifluoromethyl)-3,4-dihydro-2H-chromen-2-yl]benzoic acid;
    3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-(trifluoromethyl)-3,4-dihydro-2H-chromen-2-yl]cyclohexanecarboxylic acid;
    4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoic acid;
    3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-8-fluoro-3,4-dihydro-2H-chromen-2-yl]benzoic acid;
    4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]benzoic acid;
    4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic acid;
    rac-3-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)tetrahydro-2H-pyran-2-yl]benzoic acid;
    rac-4-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)tetrahydro-2H-pyran-2-yl]benzoic acid;
    3-[(2S,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)tetrahydro-2H-pyran-2-yl]benzoic acid;
    3-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)tetrahydro-2H-pyran-2-yl]benzoic acid;
    rac-3-[(2R,4S,6S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-phenyltetrahydro-2H-pyran-2-yl]benzoic acid;
    3-[(2S,4R,6R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-phenyltetrahydro-2H-pyran-2-yl]benzoic acid;
    3-[(2R,4S,6S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-phenyltetrahydro-2H-pyran-2-yl]benzoic acid;
    4-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)tetrahydro-2H-pyran-2-yl]benzoic acid;
    3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
    3-cyclobutyl-1-phenyl-4-{4-[(pyrrolidin-1-yl)methyl]piperidin-1-yl})-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
    5-[(2R,4R)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]pyrazine-2-carboxylic acid;
    6-[(2R,4R)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-7-(trifluoromethoxy)-3,4-dihydro-2H-1-benzopyran-2-yl]pyridine-3-carboxylic acid;
    trans-4-[(2S,4S)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-7-(trifluoromethoxy)-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic acid;
    6-[(2R,4R)-7-(difluoromethoxy)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-3,4-dihydro-2H-1-benzopyran-2-yl]pyridine-3-carboxylic acid;
    trans-4-[(2S,4S)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic acid;
    ethyl trans-4-[(2S,4S)-7-(difluoromethoxy)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylate;
    cis-4-[(2R,4R)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-7-(trifluoromethoxy)-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic acid;
    trans-4-[(2S,4S)-7-(difluoromethoxy)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic acid;
    1-[(2R,4R)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-7-(trifluoromethoxy)-3,4-dihydro-2H-1-benzopyran-2-yl]cyclopropane-1-carboxylic acid;
    trans-4-[(2R,4R)-4-{[(5S)-2,2-difluoro-5-methyl-6,7-dihydro-2H,5H-indeno[5,6-d][1,3]dioxole-5-carbonyl]amino}-7-(trifluoromethoxy)-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic acid;
    trans-4-[(2R,4R)-4-{[(5S)-2,2-difluoro-5-methyl-6,7-dihydro-2H,5H-indeno[5,6-d][1,3]dioxole-5-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic acid;
    trans-4-[(2R,4R)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic acid;
    trans-4-[(2R,4R)-7-(difluoromethoxy)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic acid; and
    trans-4-[(2R,4R)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-7-(trifluoromethoxy)-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic acid.


In one embodiment, the additional therapeutic agent is a CFTR amplifier. CFTR amplifiers enhance the effect of known CFTR modulators, such as potentiators and correctors. Examples of CFTR amplifiers are PTI130 and PTI-428. Examples of amplifiers are also disclosed in publications: WO2015138909 and WO2015138934.
In one embodiment, the additional therapeutic agent is a CFTR stabilizer. CFTR stabilizers enhance the stability of corrected CFTR that has been treated with a corrector, corrector/potentiator or other CFTR modulator combination(s). An example of a CFTR stabilizer is cavosonstat. Examples of stabilizers are also disclosed in publication: WO2012048181.
In one embodiment, the additional therapeutic agent is an agent that reduces the activity of the epithelial sodium channel blocker (ENaC) either directly by blocking the channel or indirectly by modulation of proteases that lead to an increase in ENaC activity (e.g., serine proteases, channel-activating proteases). Exemplary of such agents include camostat (a trypsin-like protease inhibitor), QAU145, 552-02, GS-9411, INO-4995, Aerolytic, amiloride, and VX-371. Additional agents that reduce the activity of the epithelial sodium channel blocker (ENaC) can be found, for example, in PCT Publication No. WO2009074575 and WO2013043720; and U.S. Pat. No. 8,999,976.
In one embodiment, the ENaC inhibitor is VX-371.
In one embodiment, the ENaC inhibitor is SPX-101 (S18).
In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents. In a particular embodiment, the additional therapeutic agents are selected from the group consisting of CFTR modulators and CFTR amplifiers. In a further embodiment, the additional therapeutic agents are CFTR modulators. In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, one potentiator, and one or more additional correctors.
This invention also is directed to kits that comprise one or more compounds and/or salts of the invention, and, optionally, one or more additional therapeutic agents.
This invention also is directed to methods of use of the compounds, salts, compositions, and/or kits of the invention to, with or without one or more additional therapeutic agents, for example, modulate the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein, and treat a disease treatable by modulating the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein (including cystic fibrosis, Sjögren's syndrome, pancreatic insufficiency, chronic obstructive lung disease, and chronic obstructive airway disease).
EXAMPLES
Chemical Synthetic Procedures
General
The compounds of the invention can be better understood in connection with the following synthetic schemes and methods which illustrate a means by which the compounds may be prepared.
The compounds of this invention can be prepared by a variety of synthetic procedures. Representative procedures are shown in, but are not limited to, Schemes 1-6. In Schemes 1-6, the variables R1, R2, R3, R4, R5 and R6 are as described in the Summary.
Optimum reaction conditions and reaction times for each individual step may vary depending on the particular reactants employed and substituents present in the reactants used. Unless otherwise specified, solvents, temperatures and other reaction conditions may be readily selected by one of ordinary skill in the art. Specific procedures are provided in the Synthetic Examples section. Reactions may be further processed in the conventional manner, e.g. by eliminating the solvent from the residue and further purified according to methodologies generally known in the art such as, but not limited to, crystallization, distillation, extraction, trituration and chromatography. Unless otherwise described, the starting materials and reagents are either commercially available or may be prepared by one skilled in the art from commercially available materials using methods described in the chemical literature.
Routine experimentations, including appropriate manipulation of the reaction conditions, reagents and sequence of the synthetic route, protection of any chemical functionality that may not be compatible with the reaction conditions, and deprotection at a suitable point in the reaction sequence of the method are included in the scope of the invention. Suitable protecting groups and the methods for protecting and deprotecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which can be found in T. Greene and P. Wuts, Protecting Groups in Organic Synthesis (3rd ed.), John Wiley & Sons, NY (1999), which is incorporated herein by reference in its entirety. Synthesis of the compounds of the invention can be accomplished by methods analogous to those described in the synthetic schemes described hereinabove and in specific examples.
Starting materials, if not commercially available, can be prepared by procedures selected from standard organic chemical techniques, techniques that are analogous to the synthesis of known, structurally similar compounds, or techniques that are analogous to the above described schemes or the procedures described in the synthetic examples section.
When an optically active form of a compound is required, it can be obtained by carrying out one of the procedures described herein using an optically active starting material (prepared, for example, by asymmetric induction of a suitable reaction step), or by resolution of a mixture of the stereoisomers of the compound or intermediates using a standard procedure (such as chromatographic separation, recrystallization or enzymatic resolution).
Similarly, when a pure geometric isomer of a compound is required, it can be prepared by carrying out one of the above procedures using a pure geometric isomer as a starting material, or by resolution of a mixture of the geometric isomers of the compound or intermediates using a standard procedure such as chromatographic separation.
The compounds of the invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e. reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) were given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
The following methods are presented with details as to the preparation of a compound of the invention as defined hereinabove and the comparative examples. A compound of the invention may be prepared from known or commercially available starting materials and reagents by one skilled in the art of organic synthesis.
All reagents were of commercial grade and were used as received without further purification, unless otherwise stated. Commercially available anhydrous solvents were used for reactions conducted under inert atmosphere. Reagent grade solvents were used in all other cases, unless otherwise specified. Column chromatography was performed on silica gel 60 (35-70 μm). Thin layer chromatography was carried out using pre-coated silica gel F-254 plates (thickness 0.25 mm). 1H NMR spectra were recorded on a Bruker Advance 300 NMR spectrometer (300 MHz) unless otherwise noted. Chemical shifts (δ) for 1H NMR spectra were reported in parts per million (ppm) relative to tetramethylsilane (δ 0.00) or the appropriate residual solvent peak, i.e. CHCl3 (δ 7.27), as internal reference. Multiplicities were given as singlet (s), doublet (d), triplet (t), quartet (q), quintuplet (quin), multiplet (m) and broad (br). Electrospray MS spectra were obtained on a Waters platform LC/MS spectrometer or with Waters Acquity H-Class UPLC coupled to a Waters Mass detector 3100 spectrometer. Columns used: Waters Acquity UPLC BEH C18 1.7 μm, 2.1 mm ID×50 mm L, Waters Acquity UPLC BEH C18 1.7 μm, 2.1 mm ID×30 mm L, or Waters Xterra® MS 5 μm C18, 100×4.6 mm. The methods were using either MeCN/H2O gradients (H2O contains either 0.1% TFA or 0.1% NH3) or Methanol/H2O gradients (H2O contains 0.05% TFA). Microwave heating was performed with a Biotage® Initiator. Electrospray MS spectra were obtained on Waters Acquity UPLC systems coupled to Waters SQD or SQD2 mass spectrometers. Columns used: Waters Acquity UPLC BEH C18 1.7 μm, 2.1 mm ID×50 mm L or Waters Acquity UPLC BEH C18 1.7 μm, 2.1 mm ID×30 mm L. The methods were using MeCN/H2O gradients (both MeCN and H2O contained either 0.1% formic acid or 0.05% NH3).
For the compounds purified by preparative chromatography, an XSelectTM CSH Prep Guard Column, C18 19×10 mm 5 m (Waters) with an XSelectTM CSH Prep OBD Column, C18 19×100 mm 5 μm (Waters) and a gradient of 0.1% formic acid in water (A) and acetonitrile (B) at a flow rate of 20 mL/minute is used. Alternatively, an XBridgeTM Prep Guard Column, C18 19×10 mm 5 m (Waters) with a XBridgeTM Prep OBD Column, C18 19×100 mm 5 m (Waters) and a gradient of 0.5% NH3 in water (A) and acetonitrile (B) at a flow rate of 20 mL/minute is used. After elution, the solvent was removed under vacuum to provide the product. For the compounds purified by preparative chromatography, an XBridgeTM Prep Guard Column, C18 19×10 mm 5 m (Waters) with a XBridgeTM Prep OBD Column, C18 30×100 mm 5 μm (Waters) and a gradient of 0.1% formic acid in water (A) and acetonitrile (B) at a flow rate of 50 mL/minute were used. Alternatively, a gradient of 0.1% DEA in water (A) and acetonitrile (B) at a flow rate of 50 mL/minute was used on the same references of guard column and column. After elution, the solvent was removed under vacuum to provide the dry product.
Alternatively, compounds were purified by automated reversed phase HPLC, using a Phenomenex® Luna® C8(2), 5 m, 100 Å, 50×30 mm, with a SecurityGuardTM 15×30 mm guard column, and a gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B), at a flow rate of 40 mL/min (0-1.0 minute 10% A, 1.0-9.0 minutes linear gradient 10-100% A, 9.0-9.5 minutes 100% A, 9.5-10.0 minutes linear gradient 100-10% A). After elution, solvent was removed under vacuum to provide the pure product.
Racemic mixtures were separated on an Agilent HP1100 system with UV detection. Column used: Chiralpak® IA (10×250 mm, 5 μm). Solvents used: iPrOH and tBME. Enantiomeric purity was determined on an Agilent HP1100 system with UV detection. Column used: Chiralpak IA (4.6×250 mm, 5 μm). Solvents used: iPrOH and tBME.
List of abbreviations used in the experimental section:











Abbreviation
Definition







Bn
benzyl


Boc
tert-butoxycarbonyl


Et
ethyl


Me
methyl


Ph
phenyl


Pr
propyl


Tf
trifluoromethanesulfonyl


OTf
trifluormethanesulfonate


DCM
dichloromethane


MeCN
acetonitrile


DMA
N,N-dimethylacetamide


DMF
N,N-dimethylformamide


AcOH or HOAc
acetic acid


eq or equiv
equivalents


TFA
trifluoroacetic acid


THF
tetrahydrofuran


NMR
nuclear magnetic resonance


DMSO
dimethyl sulfoxide


LC/MS or LCMS
liquid chromatography-mass spectrometry


EtOAc
ethyl acetate


EtOH
ethanol


MeOH
methanol


tBuOH or t-BuOH
tert-butanol


tBME or MTBE
tert-butyl methyl ether


s
singlet


br s
broad singlet


d
duplet


dd
double duplet


m
multiplet


min
minute


h
hours


mL
milliliter


μL
microliter


g
gram


mg
milligram


kg
kilogram


atm
atmosphere


w/w
weight/weight


RT
room(ambient) temperature


NEt3
triethylamine


BOP
(benzotriazol-yloxy)tris(dimethylamino)



phosphonium hexafluorophosphate


DIPEA
diisopropylethylamine


DMAP
dimethylaminopyridine


EDC
N-ethyl-N′-(3-dimethylaminopropyl)



carbodiimide


mmol
millimoles


HPLC
high pressure liquid chromatography


MS
mass spectrum


NMR
nuclear magnetic resonance


TLC
thin layer chromatography


NMP
N-methylpyrrolidone


ppm
parts per million


psi
pounds per square inch


Pd(OAc)2
palladium(II) acetate


Xantphos
4,5-bis(diphenylphosphino)-9,9-



dimethylxanthene


SM
starting material


Cpd
compound


Int
intermediate


MW
molecular weight


Mes
molecular weight measured


NA
not active


Pd(dppf)Cl2
[1,1′-



bis(diphenylphosphino)ferrocene]



dichloropalladium(II)


Pd(dppf)Cl2•CH2Cl2 or
[1,1′-


Pd(dppf)Cl2•DCM
bis(diphenylphosphino)ferrocene]



dichloropalladium(II) complex with 



dichloromethane


μm
micrometer


iPrOH
iso-propanol


DBU
1,8-diazabicycloundec-7-ene


DPPA
diphenylphosphoryl azide


LiHMDS
lithium hexamethyldisilazide or lithium



bis(trimethylsilyl)amide


rac-BINAP
rac-1,1′-binaphthyl-2,2′-diamine


TfOH
trifluoromethanesulfonic acid


Tf2O
trifluoromethanesulfonic anhydride


XPhos
2-dicyclohexylphosphino-2′,4′,6′-



triisopropylbiphenyl


XPhos Pd G1
(2-dicyclohexylphosphino-2′,4′,6′-



triisopropyl-1,1′-biphenyl)[2-(2-



aminoethyl)phenyl)]palladium(II) chloride


K2CO3
potassium carbonate


MgSO4
magnesium sulfate


NaHCO3
sodium hydrogencarbonate or sodium 



bicarbonate


Na2CO3
sodium carbonate


Na2SO4
sodium sulfate


CO
carbon monoxide


NaCl
sodium chloride


NaH
sodium hydride


LiOH
lithium hydroxide


Pd(amphos)Cl2
bis(di-tert-butyl(4-



dimethylaminophenyl)phosphine)



dichloropalladium (II)


SPhos
2-dicyclohexylphosphino-2′,6′-



dimethoxybiphenyl









SYNTHETIC PREPARATION OF THE COMPOUNDS OF THE INVENTION




General Synthetic Routes

The compounds of the invention and the comparative examples can be produced according to the following schemes.
























Method A: Synthesis of Benzyl Esters




To a solution of the carboxylic acid (1.0 equiv) in either dry DMF or dry acetonitrile is added K2CO3 (1.3 equiv) followed by benzyl bromide (1.1 equiv). The reaction mixture is heated at a temperature ranging from RT to 85° C. for 2-4 h and then partitioned between brine and either ethyl acetate or dichloromethane. The organic layer is separated, washed with brine and saturated ammonium chloride, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue is purified by flash chromatography on silica gel (eluent system: heptane/ethyl acetate) to afford the titled compound.
Illustrative Synthesis of Intermediate BE01: 1-Methyl-cyclobutanecarboxylic acid benzyl ester




To a solution of 1-methylcyclobutanecarboxylic acid (CAS: 32936-76-8, 0.5 g, 4.38 mmol, 1.0 equiv) in dry DMF was added K2CO3 (0.787 g, 5.69 mmol, 1.3 equiv) followed by benzyl bromide (CAS: 100-39-0, 0.57 mL, 4.82 mmol, 1.1 equiv). The reaction mixture was stirred at RT for 2.5 h and then diluted with ethyl acetate and brine. The organic layer was separated, washed with a saturated solution of ammonium chloride and brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (eluent system: heptane/ethyl acetate gradient from 100/0 to 90/10) to afford the titled compound.







TABLE I







List of benzyl esters












Int.
Structure
Name
SM
method
MW





BE01




1-Methyl- cyclobutanecarboxylic acid benzyl ester
 32936-76-8
A, Specific example
204


 


BE02




3-Methoxy- cyclobutanecarboxylic acid benzyl ester
552849-35-1
A
220


 


BE03




3-Fluoro- cyclobutanecarboxylic acid benzyl ester
122665-96-7
A
208


 


BE04




3-Methyl- cyclobutanecarboxylic acid benzyl ester
 87863-09-0
A
204









Method B: Cyanoketone Formation




A flame-dried round bottom flask is cooled down to RT under nitrogen. A solution of 1 M LiHMDS in THF (1.5 equiv) is introduced into the flask, and then it is cooled down to −78° C. (acetone/dry ice bath). Dry MeCN (from 1.5 to 1.7 equiv) is then added dropwise under nitrogen, and the reaction mixture is stirred for 30 min at −78° C. At this point a solution of ester (1.0 equiv) in dry THF is added dropwise, and then the reaction mixture is stirred at −78° C. for 1-2 h. The reaction mixture is quenched with cold H2O, partitioned between ethyl acetate (or diethyl ether) and H2O. The organic layer is separated, and the aqueous layer is extracted with ethyl acetate (or diethyl ether). The aqueous fraction is then acidified to pH=1 with 2 N HCl and extracted with ethyl acetate (or diethyl ether). The combined organic layers are then washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford the titled compound which is used as such or purified by flash chromatography on silica gel.
Illustrative Synthesis of CKO1: Cyclobutyl-3-oxo-propionitrile




A 1 L 4 neck round bottom flask was equipped with 2 dropping funnels and a septum on top of the apparatus. The whole system was flame-dried (heat gun) for 10 minutes under vacuum and then cooled down to RT under a positive stream of nitrogen (balloon). A low-temperature thermometer was adapted under a positive stream of nitrogen, then a 1 N LiHMDS solution in THF (468.0 mL, 468.0 mmol, 1.5 equiv) was cannulated into the flask using a positive stream of nitrogen. The solution was cooled down to −78° C. (dry ice/acetone cooling bath) as confirmed with the thermometer. Dry MeCN (24.4 mL, 468.0 mmol, 1.5 equiv) was added via syringe into the first dropping funnel, and then added dropwise (over 20 min) into the reaction mixture. After the end of the addition, the mixture was stirred at −78° C. for 1 h. At this point, cyclobutanecarboxylic acid ethyl ester (CAS: 14924-53-9, 43.1 mL, 312.1 mmol, 1.0 equiv) as a solution in dry THF (106 mL) was introduced into the second dropping funnel. This solution was slowly added over 2 h into the reaction mixture at −78° C. The mixture was stirred at −78° C. for 2 h. The reaction mixture was poured into 300 mL of cold water, stirred for 30 min and allowed to warm to RT. The mixture was then partitioned between ethyl acetate and H2O. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×300 mL). The combined organic phases were discarded. The aqueous layer was then acidified with 100 mL of 2 N HCl, then extracted with ethyl acetate (3×300 mL), washed with 50 mL of brine, dried over MgSO4, filtered and concentrated in vacuo to afford the titled compound which was used without further purification.







TABLE II







List of cyanoketones













Int.
Structure
Name
SM
method
MW
Mes





29509-06-6




4-Methyl-3-oxo- pentanenitrile


111



 


29509-06-6




4-Methyl-3-oxo- pentanenitrile


111



 


CK01, 118431-89- 3




3-Cyclobutyl-3- oxo-propionitrile
14924- 53-9
B, Specific example
123



 


59997-51-2




4,4-Dimethyl-3- oxo-pentanenitrile


125



 


887594-13- 0




3-(2-Cyano- acetyl)-azetidine-1- carboxylic acid tert-butyl ester


224



 


118431-88- 2




3-Cyclopropyl-3- oxo-propionitrile


109



 


CK02




3-(1-Methyl- cyclobutyl)-3-oxo- propionitrile
BE01
B
137
138


 


CK03




3-(cis-3-Methoxy- cyclobutyl)-3-oxo- propionitrile
BE02
B
153



 


29509-06-6




4-Methyl-3-oxo- pentanenitrile


111



 


1234616- 26-2




3-(3,3-Difluoro- cyclobutyl)-3-oxo- propionitrile


159



 


CK04




3-(3,3-Dimethyl- cyclobutyl)-3-oxo- propionitrile
3854- 83-9
B
151



 


CK05




3-(3-Fluoro- cyclobutyl)-3-oxo- propionitrile
BE03
B
141



 


CK06




3-(trans-3-Methyl- cyclobutyl)-3-oxo- propionitrile
BE04
B
137









Method C: Hydrazine Formation




Method C1: Reductive Amination
To a solution of ketone (1 equiv) and tert-butyl carbazate (CAS: 870-46-2, 1.0 equiv) in anhydrous dichloromethane at 0° C. is added acetic acid (2.0 equiv) and sodium triacetoxyborohydride (CAS: 56553-60-7, 3.0 equiv). The reaction mixture is warmed up to RT and stirred for 1 h to several days (up to 8). The reaction mixture is then basified with a solution of 2 M sodium hydroxide and a saturated solution of sodium hydrogencarbonate. The two phases are separated, and the aqueous phase is extracted with dichloromethane. The combined organic phases are washed with a saturated solution of sodium hydrogencarbonate and brine, dried over MgSO4, filtered and concentrated in vacuo to afford the tert-butoxy carbonyl hydrazine which is used as such or purified by flash chromatography on silica gel.
Method C2: Reductive Amination
To the ketone (1 equiv) in anhydrous methanol at RT is added tert-butyl carbazate (CAS: 870-46-2, 1.0 equiv). The reaction mixture is stirred for 20 minutes at RT, then acetic acid (3.0 equiv) and sodium cyanoborohydride (CAS: 25895-60-7, 1.5 equiv) are added. The reaction mixture is stirred at RT for 1 h to several days (up to 8). The reaction mixture is then basified with a solution of 2 M sodium hydroxide and a saturated solution of sodium hydrogencarbonate. The two phases are separated, and the aqueous phase is extracted with dichloromethane. The combined organic phases are washed with a saturated solution of sodium hydrogencarbonate and brine, dried over MgSO4, filtered and concentrated in vacuo to afford the tert-butoxy carbonyl hydrazine which is used as such or purified by flash chromatography on silica gel.
Method C3: Tert-Butoxy Carbonyl-Deprotection
To a solution of a tert-butoxy carbonyl hydrazine intermediate from Methods C1 or C2 in anhydrous dichloromethane at RT is added 4 M HCl in dioxane (20 equiv). The reaction mixture is stirred at RT until the reaction is finished. The solids are collected by filtration, washed twice with diethyl ether, and dried in vacuo to afford the hydrazine which is used as such.
Method C4: Tert-Butoxy Carbonyl-Deprotection
A tert-butoxy carbonyl hydrazine intermediate from Methods C1 or C2 is stirred at RT in a 1:1 mixture of dichloromethane and trifluoroacetic acid until the reaction is finished. The reaction mixture is concentrated in vacuo. The residue is taken up three times with toluene and concentrated in vacuo to afford the hydrazine which is used as such.
Illustrative Synthesis of H01: (Tetrahydro-pyran-3-yl)-hydrazine di-hydrochloride salt




Step 1: tert-butyl N-(tetrahydropyran-3-ylamino)carbamate
To a solution of dihydro-2H-pyran-3(4H)-one (CAS: 23462-75-1, 0.6 g, 5.99 mmol, 1.0 equiv) and tert-butyl carbazate (CAS: 870-46-2, 0.792 g, 5.99 mmol, 1.0 equiv) in anhydrous dichloromethane (20 mL) at 0° C. was added acetic acid (0.685 mL, 11.98 mmol, 2.0 equiv) and sodium triacetoxyborohydride (CAS: 56553-60-7, 3.81 g, 17.97 mmol, 3.0 equiv). The reaction mixture was warmed up to RT and stirred for 24 h. The reaction mixture was then basified with a solution of 2 M sodium hydroxide (45 mL) and a saturated solution of sodium hydrogencarbonate (30 mL). The two phases were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with a saturated solution of sodium hydrogencarbonate and brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (eluent system: heptane/ethyl acetate 70/30) to afford tert-butyl 2-(oxan-3-yl)hydrazine-1-carboxylate.
Step 2: (Tetrahydro-pyran-3-yl)-hydrazine di-hydrochloride salt
To a solution of tert-butyl 2-(oxan-3-yl)hydrazine-1-carboxylate from Step 1 (0.534 g, 2.46 mmol, 1 equiv) in anhydrous dichloromethane (1.74 mL) at RT was added 4 M HCl in dioxane (12.34 mL, 49.38 mmol, 20 equiv). The reaction mixture was stirred at RT overnight, and then the solid was collected by filtration. The solid was washed twice with diethyl ether and dried in vacuo to afford the titled compound, H01.
Illustrative Synthesis of H02: 4,4-Difluoro-cyclohexyl)-hydrazine bis(trifluoroacetate)




Step 1: tert-butyl N-[(4,4-difluorocyclohexyl)amino]carbamate
To 4,4-difluorocyclohexanone (CAS: 22515-18-0, 0.4 g, 2.98 mmol, 1.0 equiv) in anhydrous methanol (8.5 mL) at RT was added tert-butyl carbazate (CAS: 870-46-2, 0.394 g, 2.98 mmol, 1.0 equiv). The reaction mixture was stirred for 20 minutes at RT, and then acetic acid (0.51 mL, 8.95 mmol, 3.0 equiv) and sodium cyanoborohydride (CAS: 25895-60-7, 0.281 g, 4.47 mmol, 1.5 equiv) were added. The reaction mixture was stirred at RT overnight. The reaction mixture was then basified with a solution of 2 M sodium hydroxide (22 mL) and a saturated solution of sodium hydrogencarbonate (15 mL). The two phases were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with a saturated solution of sodium hydrogencarbonate and brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (eluent system: heptane/ethyl acetate gradient from 100/0 to 50/50) to afford tert-butyl 2-(4,4-difluorocyclohexyl)hydrazine-1-carboxylate.
Step 2: 4,4-Difluoro-cyclohexyl)-hydrazine bis(trifluoroacetate)
The tert-butyl 2-(4,4-difluorocyclohexyl)hydrazine-1-carboxylate intermediate from Step 1 (0.2 g, 0.8 mmol, 1 equiv) was stirred at RT in a 1:1 mixture of dichloromethane (0.65 mL) and trifluoroacetic acid (0.65 mL) for 1.5 h. The reaction mixture was concentrated in vacuo. The residue was taken up three times with toluene and concentrated in vacuo to afford the titled compound, H02.
Synthesis of H04: (2,4-Dimethoxy-benzyl)-hydrazine di-hydrochloride salt




Step 1: tert-butyl N-[(E)-(2,4-dimethoxyphenyl)methyleneamino]carbamate
To 2,4-dimethoxybenzaldehyde (CAS: 613-45-6, 37.82 g, 228 mmol, 1.0 equiv) in methanol at RT was added tert-butyl carbazate (CAS: 870-46-2, 30.08 g, 228 mmol, 1.0 equiv) and MgSO4 (18.9 g). The reaction mixture was stirred at RT overnight. The reaction mixture was filtered through a pad of diatomaceous earth. The solids were washed with dichloromethane, and the filtrate was concentrated in vacuo. The residue was taken up in diethyl ether (120 mL) and stirred at RT. The resulting slurry was filtered. The solid was washed three times with diethyl ether and dried in vacuo to afford tert-butyl 2-[(2,4-dimethoxyphenyl)methylidene]hydrazine-1-carboxylate.
Step 2: tert-butyl N-[(2,4-dimethoxyphenyl)methylamino]carbamate
A 2-L round bottom flask under nitrogen atmosphere was charged with methanol (1.3 L), 10% palladium on carbon (13.6 g), and tert-butyl 2-[(2,4-dimethoxyphenyl)methylidene]hydrazine-1-carboxylate from Step 1 (68.41 g, 228 mmol, 1 equiv). The reaction mixture was placed under vacuum then filled with hydrogen and kept under a hydrogen atmosphere (balloon). The reaction mixture was stirred at RT for 5 h. The reaction mixture was filtered through a pad of diatomaceous earth. The solids were washed with methanol, and the filtrate was concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (eluent system: heptane/ethyl acetate, gradient from 50/50 to 40/60) to afford tert-butyl 2-[(2,4-dimethoxyphenyl)methyl]hydrazine-1-carboxylate.
Step 3: (2,4-Dimethoxy-benzyl)-hydrazine di-hydrochloride salt
A 2-L round bottom flask was charged with tert-butyl 2-[(2,4-dimethoxyphenyl)methyl]hydrazine-1-carboxylate from Step 2 (59.8 g, 211 mmol, 1.0 equiv), then a solution of 4 M HCl in dioxane (600 mL, 2400 mmol, 11.35 equiv) was added. The reaction mixture was stirred at RT overnight. The reaction mixture was filtered. The solid was washed three times with diethyl ether and dried in vacuo to afford the titled compound, H04.







TABLE III







List of Hydrazines













Int.
Structure
Name
SM
method
MW
Mes





H01




(Tetrahydro-pyran-3- yl)-hydrazine di-hydrochloride salt
23462- 75-1
C1, C3 Specific example
116



 


H02




(4,4-Difluoro- cyclohexyl)- hydrazine di-trifluoroacetic acid salt
22515- 18-0
C2, C4 Specific example
150



 


H03




(Tetrahydro-furan-3- yl)-hydrazine di-hydrochloride salt
22929- 52-8
C2, C3
102



 


H04




(2,4-Dimethoxy- benzyl)-hydrazine di-hydrochloride salt
613-45-6
Specific example
182
183









Method D: Aryl Hydrazones Formation




R1=phenyl or 5-6 membered monocyclic heteroaryl

An aryl bromide (1.05 equiv), benzophenone hydrazone (CAS: 5350-57-2, 1.0 equiv) and rac-BINAP (CAS: 98327-87-8, 0.06 equiv) are introduced in a round bottom flask at RT and suspended in anhydrous toluene. The slurry is purged with argon (bubbling). Then palladium(II) acetate (CAS: 3375-31-3, 0.02 equiv) and sodium tert-butoxide (CAS: 865-48-5, 1.3 equiv) are added, and the resulting slurry is purged with argon again. The reaction mixture is heated at 100° C. until the reaction is finished. The reaction mixture is cooled down to RT and filtered through a pad of diatomaceous earth. Solids were washed with ethyl acetate, and the filtrate is concentrated in vacuo. The titled compound is obtained from the crude filtrate either by precipitation from a suitable solvent or by purification by flash chromatography on silica gel (eluent system: heptane/ethyl acetate).
Illustrative Synthesis of ArH01: [3-(N′-Benzhydrylidene-hydrazino)-phenyl]-dimethyl-amine




3-Bromo-N,N-dimethylaniline (CAS: 16518-62-0, 18.55 mL, 130 mmol, 1.05 equiv), benzophenone hydrazone (CAS: 5350-57-2, 24.29 g, 124 mmol, 1.0 equiv) and rac-BINAP (CAS: 98327-87-8, 4.62 g, 7.43 mmol, 0.06 equiv) were combined in a round bottom flask at RT and suspended in anhydrous toluene (80 mL). The slurry was purged with argon (bubbling), and then palladium(II) acetate (CAS: 3375-31-3, 0.556 g, 2.48 mmol, 0.02 equiv) and sodium tert-butoxide (CAS: 865-48-5, 15.46 g, 161 mmol, 1.3 equiv) were added. The resulting slurry was purged with argon again, and the reaction mixture was heated at 100° C. for 1.5 h. The reaction mixture was cooled down to RT and filtered through a pad of diatomaceous earth. The solids were washed with ethyl acetate, and the filtrate was concentrated in vacuo. The residue was taken up in diethyl ether, and stirred at RT. The resulting slurry was filtered. The collected solid was washed twice with diethyl ether and dried in vacuo to afford the titled compound.







TABLE IV







List of Arylhydrazones













Int.
Structure
Name
SM
method
MW
Mes





ArH01




[3-(N′- Benzhydrylidene- hydrazino)-phenyl]- dimethyl-amine
16518-62- 0
D Specific example
315
316


 


ArH02




N-Benzhydrylidene- N′-(3-morpholin-4- yl-phenyl)- hydrazine
197846- 82-5
D
357
358


 


ArH03




N-Benzhydrylidene- N′-(3-fluoro-5- methoxy-phenyl)- hydrazine
29578-39- 0
D
320
321


 


ArH04




N-Benzhydrylidene- N′-(6-fluoro-pyridin- 2-yl)-hydrazine
144100- 07-2
D
291
292


 


ArH05




N-Benzhydrylidene- N′-(2-chloro-pyridin- 4-yl)-hydrazine
73583-37- 6
D
308
309









Methods E1-E7: Synthesis of Aminopyrazoles
Method E1: Cyclization of Hydrazines with 3-Aminocrotononitrile




3-Aminocrotononitrile (CAS: 1118-61-2, 1.1 equiv), the hydrazine hydrochloride (1.0 equiv) and few drops of 1 N HCl solution are heated in EtOH at reflux until the reaction is finished. The reaction mixture is cooled down to RT and then is diluted with a saturated solution of sodium hydrogencarbonate. The aqueous phase is extracted with dichloromethane. The combined organic phases are filtered through a phase separator and concentrated under vacuum to afford the aminopyrazole which is used as such.
Illustrative Synthesis of AMP01: (5-Methyl-2-(3-trifluoromethoxy-phenyl)-2H-pyrazol-3-ylamine




3-Aminocrotononitrile (CAS: 1118-61-2, 0.5 g, 6.09 mmol, 1.1 eq), 3-(trifluoromethoxy)phenylhydrazine hydrochloride (1.27 g, 5.54 mmol, 1.0 equiv) and two drops of 1 N HCl solution were heated in EtOH (1.5 mL) at reflux overnight. The reaction mixture was diluted with a saturated solution of sodium hydrogencarbonate, and the aqueous phase was extracted with dichloromethane. The combined organic phases were filtered through a phase separator and concentrated under vacuum to afford the titled compound which was used as such.
Method E2: Cyclization of Hydrochloride Salts of Hydrazines with Cyano Ketones




A round bottom flask is charged with the cyanoketone (from 1.0 to 1.5 equiv), the hydrazine hydrochloride or dihydrochloride (1 equiv) and EtOH. This mixture is stirred at a temperature ranging from RT to refluxing ethanol until the reaction is finished. Then the reaction mixture is concentrated in vacuo to afford a crude mixture which is used as such or undergoes one of the following processes:
Either the crude mixture is taken up in a suitable solvent. The resulting slurry is filtered, and the solids are washed with the same solvent and dried in vacuo to afford the aminopyrazole as its hydrochloride salt which is used as such or is taken up in either ethyl acetate or dichloromethane and basified with a saturated solution of either potassium carbonate or sodium hydrogencarbonate. The two phases are separated, and the aqueous phase is extracted with either ethyl acetate or dichloromethane. The combined organic phases are washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford the aminopyrazole as its free base which is used as such or further purified by flash chromatography on silica gel.
Or alternatively this crude mixture is partitioned between water and either ethyl acetate or dichloromethane. The two phases are separated, and the aqueous phase is washed with either ethyl acetate or dichloromethane, basified with a saturated solution of sodium hydrogencarbonate and extracted with either ethyl acetate or dichloromethane. The combined organic phases are washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford the aminopyrazole as its free base which is used as such or further purified by flash chromatography on silica gel.
Illustrative Synthesis of AMP29: 5-Cyclobutyl-2-phenyl-2H-pyrazol-3-ylamine




A round bottom flask was charged with 3-cyclobutyl-3-oxo-propionitrile (CK01, 19.6 g, 159 mmol, 1.1 equiv), phenylhydrazine hydrochloride (CAS: 59-88-1, 20.92 g, 145 mmol, 1.0 equiv) and EtOH (210 mL). The reaction mixture was stirred at reflux for 1 h. Then the reaction mixture was concentrated in vacuo to afford a crude mixture which was taken up in diethyl ether. The resulting slurry was filtered, and the solid was washed with diethyl ether and dried in vacuo to afford the titled compound as its hydrochloride salt which was taken up in dichloromethane and basified with a saturated solution of sodium hydrogencarbonate. The two phases were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford the titled compound as its free base.
Illustrative Synthesis of AMP 35: 5-Cyclobutyl-2-cyclohexyl-2H-pyrazol-3-ylamine




A round bottom flask was charged with 3-cyclobutyl-3-oxo-propionitrile (CK01, [118431-89-3], 20.4 g, 166 mmol), cyclohexylhydrazine hydrochloride ([24214-73-1], 25 g, 166 mmol) and EtOH (200 mL). The reaction mixture was refluxed overnight and cooled down to RT. Next, the mixture was concentrated and water (150 mL) was added. The pH was modified till pH=7 with a saturated K2CO3 solution. Subsequently, the aqueous phase was extracted with DCM. The obtained organic phase was dried and concentrated to give a yellow solid. Trituration with MTBE gave the titled compound.
Illustrative Synthesis of AMP93: 3-cyclobutyl-1-(4-fluorophenyl)-1H-pyrazol-5-amine




A round bottom flask was charged with 3-cyclobutyl-3-oxo-propionitrile (CK01, 10 g, 81.4 mmol), 4-fluorophenylhydrazine hydrochloride ([823-85-8], 12 g, 74 mmol) and EtOH (35 mL). The reaction mixture was refluxed for 2 hours and cooled down to RT. Half of the solvent was removed in vacuo. The mixture was vigorously stirred and diisopropyl ether (350 mL) was added. The stirring was continued for 1 hour, and the formed precipitate was filtered, washed with diisopropyl ether and dried at 40° C. under reduced pressure to give the titled compound.
Illustrative Synthesis of AMP94: 1-tert-butyl-3-cyclobutyl-1H-pyrazol-5-amine




A round bottom flask was charged with 3-cyclobutyl-3-oxo-propionitrile (CK01, 12.3 g, 0.1 mol), tert-butylhydrazine hydrochloride ([7400-27-3], 13.5 g, 0.11 mol) and EtOH (150 mL). The reaction mixture was refluxed for 20 hours and cooled down to RT. Half of the solvent was removed by concentration in vacuo, and the mixture was cooled in an ice bath. The formed precipitate was collected by filtration and washed successively with diethyl ether and n-pentane. The filtrate was allowed to stand for 1 hour, and the formed precipitate was again collected by filtration and washed with diethyl ether and n-pentane. The combined solids were stirred in ethyl acetate and a saturated solution of NaHCO3. The organic phase was dried over sodium sulfate, filtered and evaporated under reduced pressure to give the titled compound.
Method E3: Cyclization of Cyano Ketones with Hydrazines Either as Free Base, Hydrochloride or TFA Salt, in the Presence of an Organic Base




To the hydrazine either as free base or as a hydrochloride or a trifluoroacetic acid mono or di-salt (1 equiv) and the cyanoketone (from 1.0 to 1.5 equiv) in ethanol or toluene at RT is added DIPEA (from 0 to 2.0 equiv). Then the reaction mixture is heated at reflux until the reaction is finished. The reaction mixture is concentrated in vacuo to afford a crude mixture which is used as such or purified by flash chromatography on silica gel to afford the aminopyrazole as its free base.
Illustrative Synthesis of AMP26: 2-Cyclopentyl-5-isopropyl-2H-pyrazol-3-ylamine




To cyclopentylhydrazine hydrochloride (CAS: 24214-72-0, 0.35 g, 2.56 mmol, 1.0 equiv) and 4-methyl-3-oxo-pentanenitrile (CAS: 29509-06-6, 0.33 mL, 2.82 mmol, 1.1 equiv) in toluene (12.8 mL) at RT was added DIPEA (0.82 mL, 5.12 mmol, 2.0 equiv). Then the reaction mixture was heated at reflux for 1.5 h. The reaction mixture was cooled down to RT and concentrated in vacuo to afford a crude mixture which was purified by flash chromatography on silica gel (eluent system: heptane/ethyl acetate gradient from 100/0 to 30/70) to afford the titled compound.
Method E4: Cyclization of Arylhydrazones with Cyanoketones




To the arylhydrazone (1 equiv) and the cyanoketone (from 1.0 to 2 equiv) in ethanol at RT is added an aqueous solution of 2 M HCl or 12 M HCl (5 equiv). Then the reaction mixture is heated at reflux until the reaction is finished. Then the reaction mixture is cooled down to RT and undergoes one of the following processes.
The reaction mixture is concentrated to dryness in vacuo to afford a crude mixture. The aminopyrazole is obtained from this crude mixture by precipitation from a suitable solvent to afford the aminopyrazole as its hydrochloride salt and used as such.
Ethanol from the reaction mixture is removed in vacuo. The resulting aqueous residue is diluted with an aqueous solution of 2 M HCl, washed with dichloromethane, then basified with a saturated solution of sodium hydrogencarbonate and extracted with dichloromethane. The combined organic phases are washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford the aminopyrazole as a free base which is used as such or further purified by flash chromatography on silica gel.
Illustrative Synthesis of AMP06: 2-(3-Dimethylamino-phenyl)-5-isopropyl-2H-pyrazol-3-ylamine




To [3-(N′-benzhydrylidene-hydrazino)-phenyl]-dimethyl-amine (ArH01, 25.57 g, 81 mmol, 1 equiv) and 4-methyl-3-oxo-pentanenitrile (CAS: 29509-06-6, 10.57 mL, 89.2 mmol, 1.1 equiv) in ethanol (255 mL) at RT was added an aqueous solution of 2 M HCl (203 mL, 405 mmol, 5 equiv). Then the reaction mixture was heated at reflux overnight. The reaction mixture was cooled down to RT, and ethanol from the reaction mixture was removed in vacuo. The resulting aqueous residue was diluted with an aqueous solution of 2 M HCl, washed with dichloromethane, then basified with a saturated solution of sodium hydrogencarbonate and extracted twice with dichloromethane. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford the titled compound which was used as such.
Method E5: SNAr on 2-(2-chloro-pyridin-4-yl)-yl-2H-pyrazol-3-ylamine Intermediates




A sealed tube is charged with the 2-(2-chloro-pyridin-4-yl)-yl-2H-pyrazol-3-ylamine intermediate (1 equiv), the amine (from 10 to 15 equiv), DIPEA (3 equiv) and DMA. This mixture is heated at a temperature ranging from 130° C. to 160° C. until the reaction is finished. Then the reaction mixture is cooled down to RT and partitioned between ethyl acetate and water. The two phases are separated and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The substituted aminopyrazole is obtained from the crude mixture either by precipitation or by purification by flash chromatography on silica gel.
Illustrative Synthesis of AMP22: 5-Isopropyl-2-(2-pyrrolidin-1-yl-pyridin-4-yl)-2H-pyrazol-3-ylamine




A sealed tube was charged with 2-(2-chloro-pyridin-4-yl)-yl-2H-pyrazol-3-ylamine intermediate (AMP20, 1.2 g, 5.07 mmol, 1 equiv), pyrrolidine (CAS: 123-75-1, 4 mL, 50.7 mmol, 10 equiv), DIPEA (2.6 mL, 15.2 mmol, 3 equiv) and DMA (10 mL). This mixture was heated at 130° C. for 2 h. Then the reaction mixture was cooled down to RT, and additional pyrrolidine (CAS: 123-75-1, 1 mL, 12.67 mmol, 2.5 equiv) was introduced, and the reaction mixture was heated at 130° C. for 30 minutes. Then the reaction mixture was cooled down to RT and partitioned between ethyl acetate and water. The two phases were separated, and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with water (three times) and brine, dried over MgSO4, filtered and concentrated in vacuo. The crude mixture was purified by flash chromatography on silica gel (eluent system: dichloromethane/methanol gradient from 100/0 to 97/3) to afford the titled compound.
Method E6: Buchwald Coupling




To the 2-(3-bromo-phenyl)-2H-pyrazol-3-ylamine hydrochloride salt intermediate (1 equiv) in anhydrous THF at RT under a nitrogen atmosphere is added the amine (1.2 equiv), a solution of 1 N LiHMDS in THF (5 equiv) and XPhos Pd G1 (CAS 1028206-56-5, 0.1 equiv). The reaction mixture is stirred at RT until the reaction is finished. The reaction mixture is hydrolyzed with a saturated solution of ammonium chloride and diluted with dichloromethane. The two phases are separated, and the aqueous phase is extracted with dichloromethane. The combined organic phases are washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The substituted aminopyrazole is obtained from the crude mixture by purification with flash chromatography on silica gel (eluent system: heptane/ethyl acetate).
Illustrative Synthesis of AMP11: 5-Isopropyl-2-(3-pyrrolidin-1-yl-phenyl)-2H-pyrazol-3-ylamine




To 2-(3-bromo-phenyl)-5-isopropyl-2H-pyrazol-3-ylamine hydrochloride salt (AMP05, 0.5 g, 1.58 mmol, 1 equiv) in anhydrous THF (5 mL) at RT under nitrogen atmosphere was added pyrrolidine (CAS: 123-75-1, 0.16 mL, 1.9 mmol, 1.2 equiv), a solution of 1 N LiHMDS in THF (8 mL, 8 mmol, 5 equiv) and XPhos Pd G1 (CAS 1028206-56-5, 0.117 g, 0.16 mmol, 0.1 equiv). The reaction mixture was stirred at RT for 5 h. The reaction mixture was treated with a saturated solution of ammonium chloride and diluted with dichloromethane. The two phases were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude mixture was purified by flash chromatography on silica gel (eluent system: heptane/ethyl acetate gradient from 100/0 to 65/35) to afford the titled compound.
Method E7: O-Alkylation of 5-aminopyrazol-3-ol analogues




A suspension of 5-aminopyrazol-3-ol derivative (1 equiv), cesium carbonate (1.2 equiv) and 2-bromopropane (1 equiv) in N-methylpyrrolidine is stirred at RT for 20 to 72 hours. The reaction mixture is diluted with DCM and washed with water. The organic phase is dried over sodium sulfate, filtered and concentrated under reduced pressure. The O-alkylated product is purified by flash column chromatography on silica gel.
Illustrative Synthesis of AMP96: 1-(4-fluorophenyl)-3-[(propan-2-yl)oxy]-1H-pyrazol-5-amine




A suspension of 5-amino-1-(4-fluorophenyl)-1H-pyrazol-3-ol ([1247169-18-1], 800 mg, 4.14 mmol), cesium carbonate (2.15 g, 4.97 mmol) and 2-bromopropane (516 μL, 4.14 mmol) in N-methylpyrrolidine (8 mL) was stirred at RT for 20 hours. The reaction mixture was diluted with DCM and washed with water. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate/n-heptane to yield the titled compound.
Synthesis of Intermediates AMP18 and AMP19: [6-(5-Amino-3-isopropyl-pyrazol-1-yl)-pyridin-2-yl]-dimethyl-amine and 5-Isopropyl-2-(6-morpholin-4-yl-pyridin-2-yl)-2H-pyrazol-3-ylamine




A sealed tube was charged with 2-(6-fluoro-pyridin-2-yl)-5-isopropyl-2H-pyrazol-3-ylamine (AMP17, 0.2 g, 0.91 mmol, 1 equiv), morpholine (CAS: 110-91-8, 0.12 mL, 1.37 mmol, 1.5 equiv), DIPEA (0.19 mL, 1.09 mmol, 1.2 equiv) and DMF (2 mL). This mixture was heated at 100° C. overnight. Then the reaction mixture was cooled down to RT and partitioned between ethyl acetate and water. The two phases were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water (three times) and brine, dried over MgSO4, filtered and concentrated in vacuo. The crude mixture was purified by flash chromatography on silica gel (eluent system: heptane/ethyl acetate gradient from 100/0 to 60/40) to afford the two titled compounds.







TABLE V







List of aminopyrazoles













Int.
Structure
Name
SM
method
MW
Mes





70373- 98-7




5-Amino-1-phenyl- 1,2-dihydro- pyrazol-3-one


175



 


826-85- 7




2-Phenyl-2H- pyrazol-3-ylamine


159



 


1131- 18-6




5-Methyl-2-phenyl- 2H-pyrazol-3- ylamine


173



 


345-07- 3




5-Methyl-2-(3- trifluoromethyl- phenyl)-2H- pyrazol-3-ylamine


241



 


866472- 29-9




2-(3-Chloro-4- methyl-phenyl)-5- methyl-2H-pyrazol- 3-ylamine


221



 


380569- 79-9




2-(2,4-Difluoro- phenyl)-5-methyl- 2H-pyrazol-3- ylamine


209



 


123279 6-65-4




2-(3,5-Difluoro- phenyl)-5-methyl- 2H-pyrazol-3- ylamine


209



 


890010- 89-6




2-(3,5-Dimethyl- phenyl)-5-methyl- 2H-pyrazol-3- ylamine


201



 


92721- 83-0




5-Methyl-2-m-tolyl- 2H-pyrazol-3- ylamine


187



 


56547- 82-1




2-Cyclohexyl-5- methyl-2H-pyrazol- 3-ylamine


179



 


40401- 41-0




2-(3-Chloro- phenyl)-5-methyl- 2H-pyrazol-3- ylamine


207



 


105438- 45-7




2-(3-Fluoro- phenyl)-5-methyl- 2H-pyrazol-3- ylamine


191



 


497141- 59-0




5-Methyl-2-(4- trifluoromethoxy- phenyl)-2H- pyrazol-3-ylamine


257



 


92721- 94-3




2-(3-Methoxy- phenyl)-5-methyl- 2H-pyrazol-3- ylamine


203



 


3524- 36-5




2-Isobutyl-5- methyl-2H-pyrazol- 3-ylamine


153



 


1124- 16-9




2-Isopropyl-5- methyl-2H-pyrazol- 3-yL amine


139



 


436088- 86-7




5-Amino-1- cyclohexyl-1H- pyrazol-3-ol


181



 


124716 9-18-1




5-Amino-1-(4- fluorophenyl)-1H- pyrazol-3-ol


193



 


AMP01




5-Methyl-2-(3- trifluoromethoxy- phenyl)-2H- pyrazol-3-ylamine
133115-55-6, 1118-61-2
E1 Specific  example
257
258


 


AMP02




2-(3,4-Difluoro- phenyl)-5-methyl- 2H-pyrazol-3- ylamine
161886-22-2, 1118-22-2
E1
209
210


 


AMP03




2-(3-Fluoro-5- methoxy-phenyl)-5- methyl-2H-pyrazol- 3-ylamine
ArH03, 1118-61-2
E4
221
222


 


AMP04




5-Isopropyl-2- phenyl-2H-pyrazol- 3-ylamine
100-63-0, 29509-06-6
E3
201
202


 


AMP05




2-(3-Bromo- phenyl)-5- isopropyl-2H- pyrazol-3-ylamine
27246-81-7, 29509-06-6
E2
280
281


 


AMP06




2-(3- Dimethylamino- phenyl)-5- isopropyl-2H- pyrazol-3-ylamine
ArH01, 29509-06-6
E4 Specific  example
244
245


 


AMP07




5-Isopropyl-2-m- tolyl-2H-pyrazol-3- ylamine
637-04-7, 29509-06-6
E2
215
216


 


AMP08




5-Isopropyl-2-(3- trifluoromethyl- phenyl)-2H- pyrazol-3-ylamine
368-78-5, 29509-06-6
E3
269
270


 


AMP09




2-(3,5-Difluoro- phenyl)-5- isopropyl-2H- pyrazol-3-ylamine
134993-88-7, 29509-06-6
E2
237
238


 


AMP10




5-Isopropyl-2-(3- morpholin-4-yl- phenyl)-2H- pyrazol-3-ylamine
ArH02, 29509-06-6
E4
286
287


 


AMP11




5-Isopropyl-2-(3- pyrrolidin-1-yl- phenyl)-2H- pyrazol-3-ylamine
AMP05
E6 Specific  example
270
271


 


AMP12




2-(3-Fluoro- phenyl)-5- isopropyl-2H- pyrazol-3-ylamine
502496-27-7, 2950906-6
E2
219
220


 


AMP13




2-(4-Fluoro- phenyl)-5- isopropyl-2H- pyrazol-3-ylamine
823-85-8, 29509-06-6
E2
219
220


 


AMP14




2-(2,4-Difluoro- phenyl)-5- isopropyl-2H- pyrazol-3-ylamine
51523-79-6, 29509-06-6
E2
237
238


 


AMP15




2-Cyclopropyl-5- methyl-2H-pyrazol- 3-ylamine
213764-25-1, 1118-61-2
E1
137
138


 


AMP16




5-Isopropyl-2-(6- methoxy-pyridin-3- yl)-2H-pyrazol-3- ylamine
179543-88-5, 29509-06-6
E2
232
233


 


AMP17




2-(6-Fluoro- pyridin-2-yl)-5- isopropyl-2H- pyrazol-3-ylamine
ArH04, 29509-06-6
E4
220
221


 


AMP18




[6-(5-Amino-3- isopropyl-pyrazol- l-yl)-pyridin-2-yl]- dimethyl-amine
AMP17
Specific  example
245
246


 


AMP19




5-Isopropyl-2-(6- morpholin-4-yl- pyridin-2-yl)-2H- pyrazol-3-ylamine
AMP17
Specific  example
287
288


 


AMP20




2-(2-Chloro- pyridin-4-yl)-5- isopropyl-2H- pyrazol-3-ylamine
ArH05, 29509-06-6
E4
237
238


 


AMP21




5-Isopropyl-2-(2- morpholin-4-yl- pyridin-4-yl)-2H- pyrazol-3-ylamine
AMP20
E5
287
288


 


AMP22




5-Isopropyl-2-(2- pyrrolidin-1-yl- pyridin-4-yl)-2H- pyrazol-3-ylamine
AMP20
E5 Specific  example
271
272


 


AMP23




2-Cyclohexyl-5- isopropyl-2H- pyrazol-3-ylamine
30929-57-8, 29509-06-6
E2
207
208


 


AMP24




2-(4,4-Difluoro- cyclohexyl)-5- isopropyl-2H- pyrazol-3-ylamine
H02, 29509- 06-6
E3
243
244


 


AMP25




5-Isopropyl-2- (tetrahydro-pyran- 3-yl)-2H-pyrazol-3- ylamine
H01, 29509-06-6
E3
209
210


 


AMP26




2-Cyclopentyl-5- isopropyl-2H- pyrazol-3-ylamine
24214-72-0, 29509-06-6
E3 Specific  example
193
194


 


AMP27




5-Isopropyl-2- (tetrahydro-furan-3- yl)-2H-pyrazol-3- ylamine
H03, 29509-06-6
E3
195
196


 


AMP28




2-(2,4-Dimethoxy- benzyl)-5- isopropyl-2H- pyrazol-3-ylamine
H04, 29509-06-6
E2
275
276


 


AMP29




5-Cyclobutyl-2- phenyl-2H-pyrazol- 3-ylamine
59-88-1, CK01
E2 Specific  example
213
214


 


AMP30




2-(3-Bromo- phenyl)-5- cyclobutyl-2H- pyrazol-3-ylamine
27246-81-7, CK01
E3
292
293


 


AMP31




5-Cyclobutyl-2-(3- pyrrolidin-1-yl- phenyl)-2H- pyrazol-3-ylamine
AMP30
E6
282
283


 


AMP32




2-(2-Chloro- pyridin-4-yl)-5- cyclobutyl-2H- pyrazol-3-ylamine
700811-29-6, CK01
E3
248
249


 


AMP33




5-Cyclobutyl-2-(2- morpholin-4-yl- pyridin-4-yl)-2H- pyrazol-3-ylamine
AMP32
E5
299
300


 


AMP34




5-Cyclobutyl-2-(2- pyrrolidin-1-yl- pyridin-4-yl)-2H- pyrazol-3-ylamine
AMP32
E5
283
284


 


AMP35




5-Cyclobutyl-2- cyclohexyl-2H- pyrazol-3-ylamine
30929-57-8, CK01
E2, Specific  Example
219
220


 


AMP36




5-Cyclobutyl-2- (2,4-dimethoxy- benzyl)-2H- pyrazol-3-ylamine
H04, CK01
E2
287
288


 


AMP37




5-tert-Butyl-2- cyclopentyl-2H- pyrazol-3-ylamine
24214-72-0, 599917-51-2
E2
207
208


 


AMP38




3-(5-Amino-1- cyclohexyl-1H- pyrazol-3-yl)- azetidine-1- carboxylic acid tert- butyl ester
30929-57-8, 887594-13-0
E2
320
321


 


AMP39




2-Cyclohexyl-5- cyclopropyl-2H- pyrazol-3-ylamine
30929-57-8, 118431-88-2
E2
205
206


 


AMP40




3-[5-Amino-1-(3,5- difluoro-phenyl)- 1H-pyrazol-3-yl]- azetidine-1- carboxylic acid tert- butyl ester
134993-88-7, 887594-13-0
E2
350
 2951


 


AMP41




5-(1-Methyl- cyclobutyl)-2- phenyl-2H-pyrazol- 3-ylamine
100-63-0, CK02
E3
227
228


 


AMP42




5-(3-Methoxy- cyclobutyl)-2- phenyl-2H-pyrazol- 3-ylamine
59-88-1, CK03
E2
243



 


AMP43




5-(3,3-Difluoro- cyclobutyl)-2- phenyl-2H-pyrazol- 3-ylamine
59-88-1, 1234616-26-2
E2
249



 


AMP44




5-(3,3-Dimethyl- cyclobutyl)-2- phenyl-2H-pyrazol- 3-ylamine
59-88-1, CK04
E2
241



 


AMP45




5-(3-Fluoro- cyclobutyl)-2- phenyl-2H-pyrazol- 3-ylamine
59-88-1, CK05
E2
231



 


AMP46




5-(trans-3-Methyl- cyclobutyl)-2- phenyl-2H-pyrazol- 3-ylamine
59-88-1, CK06
E2
 227.31



 


AMP93




3-Cyclobutyl-1-(4- fluorophenyl)-1H- pyrazol-5-amine
823-85-8, CK01
Specific  example
231
232


 


AMP94




1-tert-Butyl-3- cyclobutyl-1H- pyrazol-5-amine
7400-27-3, 118431-89-3
Specific  example
193
194


 


AMP95




1-Cyclohexyl-3- [(propan-2-yl)oxy]- 1H-pyrazol-5-amine
436088-86-7
E7
223
224


 


AMP96




1-(4-Fluorophenyl)- 3-[(propan-2- yl)oxy]-1H-pyrazol- 5-amine
1247169-18-1
E7, Specific  example
235
236





1(M − tBu + H)+






Method F: Synthesis of Aldehydes by SN—Ar




A is either CH or N

LG is F, Cl, or Br

A solution of the aldehyde (1 equiv), the amine (1.3 to 2 equiv) and the base (DIPEA or K2CO3) (2 equiv) is prepared in acetonitrile, DMSO or DMA. This mixture is heated under thermal conditions or under microwave irradiations at a temperature ranging from 85° C. to 150° C. The reaction is worked up either by filtration of the base when needed or by diluting the reaction mixture with ethyl acetate or DCM and washing the organic phase with water and brine. In all cases, the organic phase is concentrated under reduced pressure, and the crude residue is used as such or purified either by flash column chromatography or precipitation to give the titled compound.
Illustrative Synthesis of ALD02: 5′-Formyl-3,4,5,6-tetrahydro-2H-[1, 2′]bipyridinyl-4-carbonitrile




A solution of 2-chloropyridine-5-carboxaldehyde (CAS: 23100-12-1, 25.1 g, 177.4 mmol), 4-cyanopiperidine (CAS: 4395-98-6, 25.4 g, 230.6 mmol) and DIPEA (62 mL, 354.7 mmol) in acetonitrile (250 mL) was refluxed for 20 hours. The reaction mixture was cooled to RT, and the mixture was concentrated under reduced pressure. The residue was dissolved in DCM (500 mL) and washed successively with a saturated aqueous solution of Na2CO3 (250 mL) and brine (250 mL). The organic phase was stirred for 2 minutes with 10 g of silica gel, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting mixture was dissolved in DCM (150 mL) and poured into a stirring solution of diisopropyl ether (1.5 L). The mixture was stirred vigorously for 4 hours. The precipitate was collected by filtration, washed with diisopropyl ether, and dried at 40° C. under reduced pressure to give the titled compound.







TABLE VI







List of aldehydes













Int.
Structure
Name
SM
method
MW
Mes





ALD01




6-[(2-Methoxy- ethyl)-methyl- amino]-pyridine- 3-carbaldehyde
23100-12-1
F
194
195


 


ALD02




5′-Formyl- 3,4,5,6- tetrahydro-2H- [1,2′]bipyridinyl- 4-carbonitrile
23100-12-1
F, Specific example
215
216


 


ALD03




6-[Methyl- (tetrahydro- pyran-4-yl)- amino]-pyridine- 3-carbaldehyde
23100-12-1
F
220
221


 


ALD04




4-[(2-Methoxy- ethyl)-methyl- amino]- benzaldehyde
459-57-4
F
193
194


 


ALD05




1-(4-Formyl- phenyl)- piperidine-4- carbonitrile
459-57-4
F
214
215


 


ALD06




2-[Methyl- (tetrahydro- pyran-4-yl)- amino]- pyrimidine-5- carbaldehyde
933702-55-7
F
221
222


 


ALD07




1-(5-Formyl- pyrimidin-2-yl)- piperidine-4- carbonitrile
933702-55-7
F
216
217


 


ALD08




4-[Methyl- (tetrahydro- pyran-4-yl)- amino]- benzaldehyde
459-57-4
F
219
220


 


ALD09




2-[(2-Methoxy- ethyl)-methyl- amino]- pyrimidine-5- carbaldehyde
933702-55-7
F
195
196


 


ALD10




6- Dimethylamino- pyridine-3- carbaldehyde
23100-12-1
F
150
151


 


ALD11 1204-86-0




4- Morpholinobenz- aldehyde


191



 


ALD12




6-[bis(2- methoxyethyl)amino] pyridine-3- carbaldehyde
23100-12-1
F
238
239









Methods G1-G3: Synthesis of Alkylidene Pyruvate
Method G1: Synthesis of Alkylidene Pyruvate




A is either N or CH

A′ is either Re or L1-G3C as described in the Summary

A solution of potassium hydroxide (from 1.5 to 2 equiv) in water is added dropwise at 0° C. to a solution of aldehyde (1 equiv) and pyruvic acid (CAS 127-17-3, from 1 eq to 1.5 equiv) in methanol. The reaction is warmed up to RT and then heated at 40° C. for 1 h to several days. Then the reaction mixture undergoes one of the following processes:

    
    
        Either the formed precipitate is collected by filtration, suspended in an aqueous acidic solution, collected by filtration again, and dried in vacuo to give the titled compound.
        Or alternatively, methanol is removed in vacuo, and the resulting suspension is filtered. The solid is taken up in water and either ethyl acetate or dichloromethane and acidified to pH=3-5 with either acetic acid or an aqueous solution of 2 M HCl. The two phases are separated, and the aqueous phase is extracted with either ethyl acetate or dichloromethane. The combined organic phases are washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo to afford the titled compound which is used as such or further purified by precipitation.
    
    


Illustrative Synthesis of ALP19: (E)-4-(4-Bromo-phenyl)-2-oxo-but-3-enoic acid




A solution of potassium hydroxide (6.9 g, 121.6 mmol) in water (45 mL) was added at 0° C. to a stirring solution of 4-bromobenzaldehyde (CAS 1122-91-4, 15 g, 81.1 mmol) and pyruvic acid (CAS 127-17-3, 5.7 mL, 81.1 mmol) in methanol (105 mL) over a 5 minutes period. The reaction mixture was then heated at 40° C. for 4 hours, cooled down to RT and poured into ice/water (300 mL). The precipitate was stirred for 10 minutes, collected by filtration, washed with water and n-heptane, and air dried for 1 hour. The solid was suspended in aqueous 2 N HCl and stirred for 10 minutes. The precipitate was collected by filtration and dried at 40° C. under reduced pressure to afford the titled compound.
Method G2: Synthesis of Alkylidene Pyruvate




A is either N or CH

A′ is either Re or L1-G3C as described in the Summary

Triflic acid (CAS 1493-13-6, from 1.35 eq to 2.5 equiv) is added dropwise to a solution of aldehyde (1 equiv), triethyl orthoformate (CAS 122-51-0, from 1.1 eq to 1.3 equiv) and ethyl pyruvate (CAS 617-35-6, from 1.5 to 3.5 equiv) in chloroform. The solution is refluxed for 30 minutes to 24 h. The reaction mixture is cooled down to RT, diluted with dichloromethane, basified with a saturated aqueous solution of Na2CO3 or NaHCO3. The two phases are separated, and the aqueous phase is extracted with dichloromethane. The combined organic phases are dried over sodium sulfate, filtered and concentrated under reduced pressure. This crude mixture is purified either by flash chromatography on silica gel or by precipitation to afford the titled compound.
Illustrative Synthesis of ALP09: ethyl (E)-4-[6-(4-cyano-1-piperidyl)-3-pyridyl]-2-oxo-but-3-enoate




Triflic acid (CAS 1493-13-6, 26.7 mL, 301 mmol) was added dropwise to a solution of intermediate ALD02 (32.4 g, 150.5 mmol), triethyl orthoformate (CAS 122-51-0, 32.6 g, 195.7 mmol) and ethyl pyruvate (CAS 617-35-6, 41.7 mL, 376.3 mmol) in chloroform (180 mL). The solution was refluxed for 30 minutes and then cooled to RT. The reaction mixture was diluted with DCM (500 mL) and washed successively with a saturated aqueous solution of Na2CO3 (400 mL) and brine (400 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude sample was purified by flash column chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate to yield the titled compound.
Method G3: Synthesis of Alkylidene Pyruvate




In a round bottom flask, under a nitrogen atmosphere, a suspension of 4-ethynylbenzene derivative (1 equiv.), 50% ethyl glyoxalate in toluene (2 equiv), morpholine ([110-91-8], 2 equiv), copper(I) bromide ([7787-70-4], 0.5 equiv) in dioxane is heated to 85° C. for 3 to 20 hours. The reaction mixture is cooled to RT, and the solvent was evaporated under reduced pressure. The residue is suspended in a mixture of DCM or DCM/2-propanol (95/5) and is washed twice with water. The organic phase is dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude sample is purified by flash chromatography eluting with ethyl acetate/n-heptane/DCM.
Illustrative Synthesis of ALP36: ethyl 4-(4-formylphenyl)-2-oxobut-3-enoate




In a round bottom flask, under a nitrogen atmosphere, a suspension of 4-ethynylbenzaldehyde ([63697-96-1], 5 g, 38.4 mmol), 50% ethyl glyoxalate in toluene ([924-44-7], 15.7 mL, 15.7 g, 76.8 mmol), morpholine ([110-91-8], 6.7 mL, 76.8 mmol), copper(I) bromide ([7787-70-4], 2.8 g, 19.2 mmol) in dioxane (50 mL) was heated to 85° C. for 3 hours. The reaction mixture was cooled to RT, and the volatiles were removed under reduced pressure. The residue was suspended in a mixture of DCM/2-propanol (200 mL, 95/5) and washed twice with water (50 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with ethyl acetate/n-heptane to yield the titled compound.
Synthesis of ALP38: 4-Cyano-4-[4-((E)-3-ethoxycarbonyl-3-oxo-propenyl)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester




Step 1: 4-Cyano-4-{4-[(triisopropylsilanyl)-ethynyl]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester
Nitrogen was bubbled for 5 minutes through a suspension of tert-butyl 4-(4-bromophenyl)-4-cyanopiperidine-1-carboxylate ([847615-14-9], 547 mg, 1.5 mmol), tetrakis(triphenylphosphine)palladium(0) ([14221-01-3], 90 mg, 77 μmol), copper(I) iodide ([7681-65-4], 8 mg, 42 μmol), lithium chloride ([7447-41-8], 8 mg, 189 μmol), and (triisopropylsilyl)acetylene ([89343-06-6], 670 μL, 3 mmol) in triethylamine (8 mL). The tube was sealed and heated at 100° C. for 6 hours. The mixture was then concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and water. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography eluting with ethyl acetate/n-heptane to give the titled compound.
Step 2: 4-Cyano-4-(4-ethynyl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester
The compound from Step 1 (700 mg, 1.5 mmol) was dissolved in anhydrous THF (10 mL) and 1 M tetra-n-butylammonium fluoride in THF (1.7 mL, 1.7 mmol) was added. The reaction mixture was stirred at RT for 2 hours and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography eluting with ethyl acetate/n-heptane to give the titled compound.
Step 3: 4-Cyano-4-[4-((E)-3-ethoxycarbonyl-3-oxo-propenyl)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester
In a round bottom flask, under a nitrogen atmosphere, a suspension of the compound from Step 2 (270 mg, 0.58 mmol), 50% ethyl glyoxalate in toluene ([924-44-7], 232 μL, 1.16 mmol), morpholine ([110-91-8], 101 μL, 1.16 mmol), and copper(I) bromide ([7787-70-4], 42 mg, 0.29 mmol) in dioxane (5 mL) was heated to 85° C. for 20 hours. The reaction mixture was cooled down to RT and 50% ethyl glyoxalate in toluene ([924-44-7], 232 μL, 1.16 mmol), morpholine ([110-91-8], 101 μL, 1.16 mmol), and copper(I) bromide ([7787-70-4], 42 mg, 0.29 mmol) were added again, and the sealed tube was heated at 100° C. for 1 hour. The reaction mixture was cooled to RT and concentrated under reduced pressure. The residue was suspended in DCM (20 mL) and washed with water (15 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with ethyl acetate/n-heptane to yield the titled compound.







TABLE VII







List of alkylidene pyruvates













Int.
Structure
Name
SM
method
MW
Mes





ALP01




(E)-4-(4- morpholinophenyl)- 2-oxo-but-3- enoic acid
1204-86-0
G1
261
262


 


ALP02




(E)-4-[4- (dimethylamino) phenyl]-2-oxo- but-3-enoic acid
100-10-7
G1
219
220


 


ALP03




(E)-4-[2- (dimethylamino) pyrimidin-5-yl]- 2-oxo-but-3- enoic acid
55551-49-0
G1
221
222


 


ALP04




(E)-4-(2- morpholino- pyrimidin-5-yl)-2- oxo-but-3-enoic acid
842974-69-0
G1
263
264


 


ALP05




(E)-4-(6- morpholino-3- pyridyl)-2-oxo- but-3-enoic acid
173282-60-5
G1
262
263


 


ALP06




(E)-4-(4- methoxyphenyl)- 2-oxo-but-3- enoic acid
123-11-5
G1
206
207


 


ALP07




(E)-4-(6-Chloro- pyridin-3-yl)-2- oxo-but-3-enoic acid
23100-12-1
G1
211-213
212-214


 


ALP08




ethyl (E)-4-[6- [2- methoxyethyl (methyl)amino]-3- pyridyl]-2-oxo- but-3-enoate
ALD01
G2
291
292


 


ALP09




ethyl (E)-4-[6- (4-cyano-1- piperidyl)-3- pyridyl]-2-oxo- but-3-enoate
ALD02
G2, Specific example
313
314


 


ALP10




ethyl (E)-4-[6- [methyl(tetrahydro- pyran-4- yl)amino]-3- pyridyl]-2-oxo- but-3-enoate
ALD03
G2
318
319


 


ALP11




ethyl (E)-4-[4- [2- methoxyethyl (methyl)amino] phenyl]-2-oxo-but- 3-enoate
ALD04
G2
291
292


 


ALP12




ethyl (E)-4-[4- (4-cyano-1- piperidyl)phenyl]- 2-oxo-but-3- enoate
ALD 05
G2
312
313


 


ALP13




ethyl (E)-4-[2- [methyl(tetrahydro- pyran-4- yl)amino]pyrimidin- 5-yl]-2-oxo- but-3-enoate
ALD06
G2
319
320


 


ALP14




ethyl (E)-4-[2- (4-cyano-1- piperidyl)pyrimidin- 5-yl]-2-oxo- but-3-enoate
ALD07
G2
314
315


 


ALP15




ethyl (E)-4-[4- [methyl(tetrahydro- pyran-4- yl)amino]phenyl]- 2-oxo-but-3- enoate
ALD08
G2
317
318


 


ALP16




ethyl (E)-4-[2- [2- methoxyethyl (methyl)amino] pyrimidin-5-yl]-2- oxo-but-3- enoate
ALD09
G2
293
294


 


ALP17




ethyl (E)-4-(2,6- difluoro-4- methoxy- phenyl)-2-oxo- but-3-enoate
256417-10-4
G2
270
271


 


ALP18




(E)-4-(4- Morpholin-4-yl- phenyl)-2-oxo- but-3-enoic acid ethyl ester
ALD11, 1204-86-0
G2
289
290


 


ALP19




(E)-4-(4-Bromo- phenyl)-2-oxo- but-3-enoic acid
1122-91-4
G1, Specific example
254-256
255-257


 


ALP20




(E)-4-(6- Dimethylamino- pyridin-3-yl)-2- oxo-but-3-enoic acid ethyl ester
ALD10
G2
248
249


 


ALP21




(E)-4-(6- Dimethylamino- pyridin-3-yl)-2- oxo-but-3-enoic acid
ALD10
G1
220
221


 


ALP22




(E)-4-(2- Morpholin-4-yl- pyrimidin-5-yl)- 2-oxo-but-3- enoic acid ethyl ester
842974-69-0
G2
291
292


 


ALP23




(E)-4-{6-[Bis- (2-methoxy- ethyl)-amino]- pyridin-3-yl}-2- oxo-but-3-enoic acid ethyl ester
ALD12
G2
336
337


 


ALP24




(E)-4-(4- Acetylamino- phenyl)-2-oxo- but-3-enoic acid ethyl ester
122-85-0
G2
261
262


 


ALP25




(E)-4-(4- Dimethylamino- phenyl)-2-oxo- but-3-enoic acid ethyl ester
100-10-7
G2
247
248


 


ALP26




(E)-4-(6- Morpholin-4-yl- pyridin-3-yl)-2- oxo-but-3-enoic acid ethyl ester
173282-60-5
G2
290
291


 


ALP36




ethyl 4-(4- formylphenyl)- 2-oxobut-3- enoate
63697-96-1
G3, Specific example
232



 


ALP38




4-Cyano-4-[4- ((E)-3- ethoxycarbonyl- 3-oxo- propenyl)- phenyl]- piperidine-1- carboxylic acid tert-butyl ester
847615-14-9
Specific example
412
NA









Methods H1-H3: Synthesis of Halogenated Pyrazolopyridine
Method H1: Synthesis of Halogenated Pyrazolopyridine (Route 1)
Illustrative Synthesis of HP01: ethyl 4-chloro-3-isopropyl-1-(m-tolyl)pyrazolo[3,4-b]pyridine-6-carboxylate







Step 1: 6-Hydroxy-3-isopropyl-1-m-tolyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester
5-Isopropyl-2-m-tolyl-2H-pyrazol-3-ylamine hydrochloride (AMP07, 14.97 g, 59.7 mmol) was dissolved in AcOH (100 mL). Diethyloxalacetate sodium salt (CAS: 40876-98-0, 15 g, 71.6 mmol, 1.2 equiv) was added, and the reaction mixture was refluxed overnight. The reaction mixture was cooled down to RT, poured into water (400 mL) and diluted with ethyl acetate. The two phases were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic layers were concentrated in vacuo, and the resulting residue was taken up twice with cyclohexane (2×200 mL) and concentrated in vacuo again. The residue was suspended in a mixture of ethanol/water (100 mL/20 mL), and the resulting precipitate was collected by filtration and washed with heptane. The solid was dried under vacuum to provide the titled compound.
Step 2: 3-Isopropyl-1-m-tolyl-6-trifluoromethanesulfonyloxy-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester
6-Hydroxy-3-isopropyl-1-m-tolyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester (14.25 g, 42 mmol) was suspended in acetonitrile under nitrogen atmosphere. Pyridine (3.8 mL, 46.2 mmol, 1.1 equiv) was added. The reaction mixture was cooled to 0° C., and trifluoromethanesulfonic anhydride (CAS 358-23-6, 7.8 mL, 46.2 mmol, 1.1 equiv) was added dropwise over 20 min. The reaction mixture was then warmed up to RT over 20 min. Water was added (200 mL), and the suspension was filtered. The solid was washed successively with water and ethanol (40 mL) and then dried in vacuo to afford the titled compound.
Step 3: 6-Iodo-3-isopropyl-1-m-tolyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester
3-Isopropyl-1-m-tolyl-6-trifluoromethanesulfonyloxy-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester (13.0 g, 27.6 mmol) was suspended in acetonitrile. Sodium iodide (20.7 g, 138 mmol, 5 equiv) was added. The reaction mixture was cooled to 0° C., trifluoromethanesulfonic acid (5.4 mL, 60.7 mmol, 2.2 equiv) was added dropwise. The reaction mixture was stirred at RT overnight. At this point, the reaction was not complete and additional trifluoromethanesulfonic acid (2 mL, 22.6 mmol, 0.8 equiv) was added and stirring was continued for 1 hour. Water was added to the reaction mixture, and the suspension was filtered. The solid was washed with ethanol (10 mL) and dried in vacuo to afford the titled compound.
Step 4: 6-Iodo-3-isopropyl-1-m-tolyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid
6-Iodo-3-isopropyl-1-m-tolyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester (8.73 g, 4.63 mmol) was suspended in ethanol (10 mL). An aqueous solution of 2 M sodium hydroxide (10 mL, 20 mmol, 4.3 equiv) was added, and the reaction mixture was stirred at 70° C. until complete conversion. Then the reaction mixture was cooled down to 0° C., and an aqueous solution of 2 M HCl was added until pH<2 was reached. The resulting suspension was filtered, and the solid was dried in vacuo to afford the titled compound.
Step 5: (6-Iodo-3-isopropyl-1-m-tolyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-carbamic acid tert-butyl ester
6-Iodo-3-isopropyl-1-m-tolyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (8.12 g, 19.3 mmol) was suspended in toluene (43 mL). tert-Butanol (3.1 mL, 32.6 mmol, 2.0 equiv), triethylamine (4.54 mL, 32.6 mmol, 2.0 equiv) and diphenylphosphoryl azide (CAS 26386-88-9, 5 mL, 23.1 mmol, 1.2 equiv) were successively added. The reaction mixture was refluxed for 30 minutes. The reaction mixture was cooled down to RT and partitioned between ethyl acetate and water. The aqueous phase was further extracted with ethyl acetate. The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was suspended in ethanol. The resulting precipitate was collected by filtration, washed with ethanol and dried under vacuum to provide the titled compound.
Step 6: (6-Cyano-3-isopropyl-1-m-tolyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-carbamic acid tert-butyl ester
(6-Iodo-3-isopropyl-1-m-tolyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-carbamic acid tert-butyl ester (7.56 g, 15.4 mmol) was solubilized in dry dimethylformamide (20 mL) in a sealed vial. Zinc cyanide (CAS 557-21-1, 1.1 g, 9.2 mmol, 0.6 equiv) was added, and the reaction mixture was degassed with argon (bubbling) for 5 minutes.
Tetrakis(triphenylphosphine)palladium(0) (CAS 14221-01-3, 0.9 g, 0.77 mmol, 0.05 equiv) was added, and the reaction mixture was degassed again with argon (bubbling) for 5 minutes. The vial was sealed, and the reaction mixture was stirred at 110° C. for 2 hour. The reaction mixture was cooled down to room temperature and diluted with water and ethyl acetate. The aqueous phase was further extracted with ethyl acetate. The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated to a volume of 10 mL. Ethanol (10 mL) was added, and the suspension was stirred at 0° C. for 10 min. The resulting precipitate was collected by filtration, washed with ethanol and dried under vacuum to provide the titled compound.
Step 7: 4-Amino-3-isopropyl-1-m-tolyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid hydrochloride salt
(6-Cyano-3-isopropyl-1-m-tolyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-carbamic acid tert-butyl ester (4.8 g, 12.26 mmol) was suspended in 6 M HCl (50 mL). The reaction mixture was refluxed for 24 h. The reaction mixture was cooled to 0° C., and the obtained suspension was filtered. The solid was washed with diisopropyl ether and dried in vacuo to yield the titled compound.
Step 8: 4-Amino-3-isopropyl-1-m-tolyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid ethyl ester
4-Amino-3-isopropyl-1-m-tolyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid hydrochloride salt (4.23 g, 12.26 mmol) was solubilized in ethanol (150 mL). Thionyl chloride (CAS 7719-09-7, 1.34 mL, 18.39 mmol, 1.5 equiv) was carefully added. The reaction mixture was refluxed for 24 hours. The reaction mixture was cooled down to RT and concentrated in vacuo. The residue was taken up in ethanol (85 mL) and thionyl chloride (CAS 7719-09-7, 2.32 mL, 31.86 mmol, 2.6 equiv) was carefully added at RT. The mixture was refluxed for 6 hours. The reaction mixture was cooled down to RT and concentrated in vacuo. The crude mixture was diluted with ethyl acetate, basified with a saturated solution of sodium hydrogencarbonate. This mixture was filtered through a pad of Celpure® P65. Solids were washed with ethyl acetate. The two phases of the filtrate were separated, and the aqueous fraction was further extracted with ethyl acetate. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluent system: heptane/ethyl acetate gradient from 95/5 to 80/20) to afford the titled compound.
Step 9: 4-Chloro-3-isopropyl-1-m-tolyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid ethyl ester
Copper (II) chloride (CAS 7447-39-4, 1.045 g, 7.77 mmol, 1.0 equiv) was suspended in acetonitrile (33 mL). Isopentylnitrite (CAS 110-46-3, 1.57 mL, 11.65 mmol, 1.5 equiv) was added, and the reaction mixture was stirred at RT for 30 minutes. 4-Amino-3-isopropyl-1-m-tolyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid ethyl ester (2.63 g, 7.77 mmol, 1.0 equiv) was added. The reaction mixture was stirred at 75° C. for 2.5 h. The reaction mixture was cooled down to 0° C., and the resulting suspension was filtered. The solid was washed with cold acetonitrile and dried in vacuo to afford the titled compound. The filtrate was concentrated in vacuo and purified by flash chromatography on silica gel (eluent system: heptane/ethyl acetate gradient from 100/0 to 98/2) to provide additional titled compound.
Method H1′: Alternative Conditions for Chlorination Route 1 Step 9




To the 4-amino intermediate (1 equiv) in acetonitrile at RT is added isopentylnitrite (CAS 110-46-3, from 3 to 6 eq) followed by copper(I) chloride (CAS 7758-89-6, from 3 to 6 equiv), and the reaction mixture is stirred at RT for 1 h to 24 h. The reaction mixture is diluted with dichloromethane and with a saturated solution of sodium hydrogencarbonate. The two phases are separated, and the aqueous phase is extracted with dichloromethane. The combined organic phases are washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue is purified by flash chromatography on silica gel to afford the titled compound.
Illustrative Synthesis of HP03: ethyl 4-chloro-1-[3-(dimethylamino)phenyl]-3-isopropyl-pyrazolo[3,4-b]pyridine-6-carboxylate




To 4-amino-1-(3-dimethylamino-phenyl)-3-isopropyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid ethyl ester (1 g, 2.74 mmol, 1 equiv) in acetonitrile (10 mL) at RT was added isopentylnitrite (CAS 110-46-3, 1.1 mL, 8.21 mmol, 3 equiv) followed by copper(I) chloride (CAS 7758-89-6, 0.82 g, 8.21 mmol, 3 equiv), and the reaction mixture was stirred at RT for 1 h. The reaction mixture was diluted with dichloromethane and with a saturated solution of sodium hydrogencarbonate. The two phases were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (eluent system: heptane/ethyl acetate gradient from 100/0 to 90/10) to afford the titled compound.
Synthesis of HP13: ethyl 4-chloro-3-methyl-1-phenyl-pyrazolo[3,4-b]pyridine-6-carboxylate







Step 1: 6-Hydroxy-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester
5-Amino-3-methyl-1-phenylpyrazole (CAS: 1131-18-6, 6.83 g, 39.4 mmol) was dissolved in AcOH (70 mL). Diethyloxalacetate sodium salt (CAS: 40876-98-0, 9.12 g, 44.4 mmol, 1.1 equiv) was added, and the reaction mixture was refluxed until complete conversion. The reaction mixture was concentrated in vacuo, and the residue was taken up in cyclohexane (2×100 mL) and concentrated in vacuo again. The residue was suspended in a mixture of MeOH/water (150 mL/100 mL). The resulting precipitate was collected by filtration and washed with heptane. The solid was dried under vacuum to provide the titled compound.
Step 2: 6-Bromo-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester
6-Hydroxy-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester (7.27 g, 24.5 mmol) was solubilized in anisole (30 mL). Phosphorous(V) oxybromide (CAS 7789-59-5, 8.23 g, 29.3 mmol, 1.2 equiv) was added, and the reaction mixture was refluxed at 140° C. for 1 h. The reaction mixture was cooled down to room temperature and basified with a saturated solution of sodium hydrogencarbonate. The reaction mixture was extracted twice with ethyl acetate, and the combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by filtration on a pad of silica gel (200 g), heptane/EtOAc 100/0 to 90/10) to give the titled compound.
Step 3: 6-Bromo-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid
6-Bromo-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester (3.90 g, 10.8 mmol) was suspended in ethanol (20 mL). An aqueous solution of 1 M sodium hydroxide (20 mL, 20 mmol, 1.9 equiv) was added, and the reaction mixture was stirred at 70° C. for 30 min. The reaction mixture was then concentrated in vacuo. The residue was acidified with an aqueous solution of 2 M HCl and extracted with ethyl acetate. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo to yield the titled compound.
Step 4: (6-Bromo-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-carbamic acid tert-butyl ester
6-Bromo-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (3.50 g, 10.4 mmol) was suspended in toluene (35 mL). tert-Butanol (2 mL, 21.6 mmol, 2.1 equiv), triethylamine (4.4 mL, 31.2 mmol, 3.0 equiv) and diphenylphosphoryl azide (CAS 26386-88-9, 3.2 mL, 14.8 mmol, 1.4 equiv) were successively added. The reaction mixture was refluxed for 1.5 h. The reaction mixture was cooled down to RT and concentrated in vacuo, then partitioned between ethyl acetate and water. The aqueous phase was further extracted with ethyl acetate. The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by filtration on a pad of silica gel (200 g, heptane/EtOAc 100/0 to 90/10) to give the titled compound.
Step 5: (6-Cyano-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-carbamic acid tert-butyl ester
(6-Bromo-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-carbamic acid tert-butyl ester (4.16 g, 10.3 mmol) was solubilized in dry dimethylformamide (20 mL) in a sealed vial. Zinc cyanide (CAS 557-21-1, 0.727 g, 6.2 mmol, 0.6 equiv) was added, and the reaction mixture was degassed with argon for 5 minutes. Tetrakis(triphenylphosphine) palladium(0) (CAS 14221-01-3, 0.595 g, 0.5 mmol, 0.05 equiv) was added, and the vial was sealed. The reaction mixture was stirred at 100° C. for 1 hour. The reaction was not complete. Additional tetrakis(triphenylphosphine)palladium(0) (CAS 14221-01-3, 0.595 g, 0.5 mmol, 0.05 equiv) and zinc cyanide (CAS 14221-01-3, 0.485 g, 4.1 mmol, 0.4 equiv) were added at RT, and the vial was sealed again. The reaction mixture was stirred at 100° C. for one hour and cooled down to room temperature. Water was added to the reaction mixture and precipitation occurred. The suspension was filtered, and the cake was washed with water. The solid residue was taken up with dichloromethane and with an aqueous solution of 0.5 M NaOH. The organic phase was separated, dried over Na2SO4, filtered and concentrated. The residue was purified by filtration on a pad of silica gel (150 g, heptane/EtOAc 100/0 to 60/40) to give the titled compound mixed with (6-cyano-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-carbonitrile. The mixture was engaged in the next step without further purification.
Step 6: 4-Amino-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid hydrochloride salt
A mixture of (6-cyano-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-carbamic acid tert-butyl ester and (6-cyano-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-carbonitrile (3.5 g) was suspended in 6 M HCl (50 mL). The reaction mixture was refluxed for 18 h. The reaction mixture was cooled to 0° C. and the obtained suspension was filtered. The solid was washed with an aqueous solution of 0.1 M HCl. The filtrate was concentrated in vacuo and precipitation occurred. The solid was also collected by filtration. The combined solids were dried in vacuo to yield the titled compound.
Step 7: 4-Amino-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid ethyl ester
4-Amino-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid hydrochloride salt (2.03 g, 7.6 mmol) was solubilized in ethanol (40 mL). Thionyl chloride (CAS 7719-09-7, 1.16 mL, 15.9 mmol, 2.1 equiv) was carefully added. The reaction mixture was refluxed for 24 hours. The reaction mixture was concentrated in vacuo and partitioned between ethyl acetate and aqueous saturated NaHCO3. The aqueous phase was further extracted with ethyl acetate. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo to give the titled compound.
Step 8: 4-Chloro-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid ethyl ester
Copper (II) chloride (CAS 7447-39-4, 0.908 g, 6.75 mmol, 1.0 equiv) was added to acetonitrile (50 mL). Isopentylnitrite (CAS 110-46-3, 1.4 mL, 10.1 mmol, 1.5 equiv) was added, and the reaction mixture was stirred at 75° C. for 5 minutes. 4-Amino-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid ethyl ester (2.0 g, 6.75 mmol, 1.0 equiv) dissolved in acetonitrile (50 mL) was added. The reaction mixture was stirred at 75° C. for 2.5 h. The reaction mixture was cooled down and concentrated in vacuo. Water was added to the residue, and the mixture was extracted with ethyl acetate. Copper salts prevented clean extraction. The suspension was filtered through diatomaceous earth. The organic phase was dried over Na2SO4, filtered and concentrated. The residue was suspended in ethanol (10 mL) and filtered. The solid was dried in vacuo to give the titled compound. The copper salts on the diatomaceous earth were washed with dichloromethane. The filtrate was concentrated to provide additional titled compound.
Method H2: Synthesis of Halogenated Pyrazolopyridine (Route 2)
Illustrative Synthesis of HP02: methyl 4-chloro-3-cyclobutyl-1-phenyl-pyrazolo[3,4-b]pyridine-6-carboxylate




Step 1: 3-cyclobutyl-1-phenyl-pyrazolo[3,4-b]pyridine-4,6-diol
To a mixture of 3-cyclobutyl-1-phenyl-1H-pyrazol-5-amine (AMP29, 74.0 g, 347 mmol) in oxydibenzene (450.0 g, 2.64 mol) was added diethyl malonate (CAS 105-53-3, 139.0 g, 867 mmol). The system was heated at 130-150° C. for 40 h. By this time solid had precipitated and heating was stopped. Two more reactions were set up as described above. All three reaction mixtures were combined. The combined mixture was cooled to below 40° C. and diluted with about 1.8 L of diethyl ether, and the resulting suspension was stirred for 2 h and then filtered. The collected solids were rinsed with diethyl ether (1 L). The solids were dried on the filter to give the titled compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.28 (s, 1H), 8.18 (d, J=7.9 Hz, 2H), 7.58-7.39 (m, 2H), 7.21 (t, J=7.1 Hz, 1H), 5.85 (s, 1H), 3.88 (quin, J=8.4 Hz, 1H), 2.44-2.22 (m, 4H), 2.07-1.78 (m, 2H).
Step 2: 4, 6-dichloro-3-cyclobutyl-1-phenyl-pyrazolo[3,4-b]pyridine
A mixture of 3-cyclobutyl-1-phenyl-pyrazolo[3,4-b]pyridine-4,6-diol (60.0 g, 213 mmol) in phenyl dichlorophosphate (CAS 770-12-7,135 g, 640 mmol) was stirred at 170° C. for 15 h. Two more reactions were set up as described above. All three reaction mixtures were combined and poured into ice water (5 L) keeping the internal temperature <10° C. The mixture was neutralized with concentrated NH4OH (500 mL) to pH 6 ̃7, then the suspension was stirred for 2 h. As the pH increased and with continued stirring, the semi-solid suspension becomes a flowing solid. The solid was collected by filtration. The wet solid was dissolved in dichloromethane (3 L) and filtered through a short path of silica gel (2 kg), eluting with dichloromethane (15 L). The filtrate was concentrated to a solid which was triturated with acetonitrile (1.5 L) and collected by filtration to give the titled compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.20 (d, J=7.9 Hz, 2H), 7.51 (t, J=7.5 Hz, 2H), 7.35-7.27 (m, 1H), 7.16 (s, 1H), 4.15 (quin, J=8.4 Hz, 1H), 2.63-2.41 (m, 4H), 2.20-2.07 (m, 1H), 2.00 (s, 1H).
Step 3: methyl 4-chloro-3-cyclobutyl-1-phenyl-pyrazolo[3,4-b]pyridine-6-carboxylate
To a mixture of 4,6-dichloro-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine (50.0 g, 157 mmol) in methanol (700 mL) was added triethylamine (31.8 g, 314 mmol) and Pd(dppf)Cl2.DCM (CAS 95464-05-4, 6.4 g, 7.86 mmol). The system was heated at 60° C. under CO (30 psi) for 40 h. Two more reactions were set up as described above. All three reaction mixtures were combined and concentrated to give a semisolid which was dissolved in dichloromethane (3 L) and filtered through a 2 kg plug of silica gel. After concentration, about 130 g of solid was obtained. This solid was taken up in 1.3 L of ethyl acetate with heating. This solution was stirred at room temperature. Solids came out over a couple of minutes, and then 1.3 L of hexane was added in a thin stream via addition funnel with stirring for 2 hours. The solids were collected by filtration to give the titled compound. 1H NMR (400 MHz, CDCl3) δ ppm 8.38-8.27 (m, 2H), 7.95 (s, 1H), 7.53 (t, J=7.9 Hz, 2H), 7.35-7.27 (m, 1H), 4.21 (q, J=8.6 Hz, 1H), 4.08-4.03 (m, 1H), 2.66-2.40 (m, 4H), 2.22-1.93 (m, 2H).
Illustrative Synthesis of HP19: Methyl 4-chloro-3-cyclobutyl-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylate




Step 1: 3-Cyclobutyl-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-4,6-diol
A mixture of 3-cyclobutyl-1-(4-fluorophenyl)-1H-pyrazol-5-amine (AMP93, 5 g, 18.6 mmol) and diethyl malonate ([105-53-3], 8.5 mL, 55.8 mmol) was heated at 100° C. for 30 minutes and then at 170° C. for 3 hours. The reaction mixture was cooled down to RT and dissolved in dichloromethane (60 mL). The resultant solution was poured into a stirred solution of n-heptane (700 mL). The precipitate was collected by filtration, washed with n-heptane and dried at 40° C. under reduced pressure to give the titled compound.
Step 2: 4, 6-Dichloro-3-cyclobutyl-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine
A three-neck round-bottom flask equipped with a Dean-Stark apparatus was charged with phenyl dichlorophosphate ([770-12-7], 854 g, 4.05 mol). 3-Cyclobutyl-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-4,6-diol (404 g, 1.35 mol) was added in portions over a period of 5 minutes. The temperature was increased to 170° C. over a period of 1 hour, and the stirring at 170° C. was continued for 21 hours. The reaction mixture was cooled down to 50° C. and added slowly to a stirred aqueous 4 N NaOH (5 L) keeping the temperature below 20° C. The suspension was stirred for 1 hour at 10-15° C., and then cold water (3 L) was added. The precipitate was collected by filtration, washed with water and dried at 40° C. under reduced pressure to give the titled compound.
Step 3: methyl 4-chloro-3-cyclobutyl-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylate
A pressured vessel was charged with 4,6-dichloro-3-cyclobutyl-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine (5 g, 14.9 mmol), Pd(dppf)Cl2.DCM (CAS 95464-05-4, 218 mg, 0.3 mmol), and sodium acetate (1.8 g, 22.3 mmol) in dioxane/methanol (1:1, 25 mL). The system was loaded with CO (4 bars) and heated at 40° C. for 2 hours. The vessel was cooled to RT, and the conversion was monitored by LCMS. The reaction vessel was charged again with CO (4 bars) and heated at 40° C. The sequence was repeated until full conversion was observed. The crude mixture was concentrated under reduced pressure and purified by flash column chromatography eluting with a mixture of n-heptane/dichloromethane (90/10 to 30/70) to give the titled compound.
Illustrative Synthesis of HP25: methyl 4-chloro-3-cyclobutyl-1-cyclohexyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylate




Step 1: 3-cyclobutyl-1-cyclohexyl-4-hydroxy-3aH-pyrazolo[3,4-b]pyridin-6-one
A mixture of 5-cyclobutyl-2-cyclohexyl-2H-pyrazol-3-ylamine (AMP35, 10 g, 45.7 mmol) and diethyl malonate ([105-53-3], 27.7 mL, 183 mmol) in diphenylether (50 mL) was heated at 130° C. over approximately 60 hours. The reaction mixture was cooled down to RT and quenched with 0.5 M NaOH solution (100 mL, 50 mmol). Extraction with EtOAc gave an aqueous phase that was acidified with a 12 M HCl solution (4.3 mL, 51.6 mmol) giving rise to a suspension. This suspension was extracted with EtOAc. The obtained organic layer was dried and concentrated to give the titled compound that was used as such.
Step 2: 4, 6-dichloro-3-cyclobutyl-1-cyclohexyl-pyrazolo[3,4-b]pyridine
The 3-cyclobutyl-1-cyclohexyl-4-hydroxy-3 aH-pyrazolo[3,4-b]pyridin-6-one (5.15 g, 17.9 mmol) was suspended in phenyl dichlorophosphate ([770-12-7], 8.01 mL, 53.8 mmol). The mixture was heated at 130° C. overnight. Next, the mixture was diluted in DCM and poured into ice water. After increasing the pH till 7-8 with a 20% NH4OH solution, the biphasic mixture was stirred for 30 minutes. Subsequently, the organic phase was separated, dried and concentrated to give a residue. This residue was purified by chromatography using a petroleum ether/EtOAc gradient (100/0 to 90/10). This resulted in the titled compound that was used as such.
Step 3: methyl 4-chloro-3-cyclobutyl-1-cyclohexyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylate
In a Parr apparatus, 4,6-dichloro-3-cyclobutyl-1-cyclohexyl-pyrazolo[3,4-b]pyridine (2.17 g, 6.72 mmol) was dissolved in MeOH (50 mL) together with Pd(dppf)Cl2.DCM (CAS 95464-05-4, 275 mg, 0.33 mmol) and triethylamine (1.87 mL, 13.4 mmol). The system was loaded with CO (5 bar) and heated at 45° C. for 18 hours. After cooling down the mixture till RT, the mixture was concentrated, and the obtained residue was purified by chromatography using a petroleum ether/EtOAc gradient (100/0 till 95/5). This yielded the titled compound.
Method H3: Synthesis of Halogenated or Sulfonylated Pyrazolopyridine (Route 3)




Step 1: Diethyl but-2-Enedioate
To a suspension of aminopyrazole (1 equiv) in ethanol (150 mL) is added diethyl acetylenedicarboxylate (1.1 equiv). The reaction mixture is stirred at room temperature for 4 hours. The reaction mixture is concentrated. The crude residue is purified by silica gel column chromatography (heptane/EtOAc 100/0 to 70/30) to give the titled compound.
Step 2: Pyrazolopyridine Formation
The diethyl but-2-enedioate is heated under air atmosphere at 190-195° C. for one hour. The reaction mixture is cooled to room temperature and is partitioned between dichloromethane and water. The aqueous phase is separated and extracted two times with dichloromethane. The combined organic phases were dried, filtered and concentrated in vacuo. The crude residue can be purified by silica gel column chromatography to provide the pyrazolopyridine.
Step 3: Chlorination
A solution of the above pyrazolopyridine (1 equiv) in phosphorus(V) oxychloride (32 equiv) was stirred at 115° C. for 1 h. The reaction mixture is then cooled to room temperature and concentrated in vacuo. The residue is dissolved in ethyl acetate, and the reaction mixture is added dropwise to a solution of saturated of sodium hydrogencarbonate till total neutralization of phosphorus(V) oxychloride (pH 8). The aqueous phase is separated and extracted two times with ethyl acetate. The combined organic phases are washed with brine, dried, filtered and concentrated in vacuo. The crude residue can be purified by silica gel column chromatography to provide the chlorinated pyrazolopyridine from which the dimethoxybenzyl group has also been removed.
Illustrative Synthesis of HP08: 4-Chloro-3-isopropyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid ethyl ester




Step 1: 2-[2-(2,4-Dimethoxy-benzyl)-5-isopropyl-2H-pyrazol-3-ylamino]-but-2-enedioic acid diethyl ester
To a suspension of 2-(2,4-dimethoxy-benzyl)-5-isopropyl-2H-pyrazol-3-ylamine (AMP28, 18.14 g, 65.88 mmol) in ethanol (150 mL) was added diethyl acetylenedicarboxylate (CAS: 762-21-0, 11.60 mL, 72.47 mmol). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated. The crude residue was purified by silica gel column chromatography (heptane/EtOAc 100/0 to 70/30) to give the titled compound.
Step 2: Compound HP06: 1-(2,4-Dimethoxy-benzyl)-4-hydroxy-3-isopropyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid ethyl ester
2-[2-(2,4-Dimethoxy-benzyl)-5-isopropyl-2H-pyrazol-3-ylamino]-but-2-enedioic acid diethyl ester (13.46 g, 30.21 mmol) was heated under air atmosphere at 190-195° C. for one hour. The reaction mixture cooled to room temperature and was partitioned between dichloromethane and water. The aqueous phase was separated and extracted two times with dichloromethane. The combined organic phases were dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (heptane/EtOAc 100/0 to 60/40) to provide the titled compound.
Step 3: Compound HP08: 4-Chloro-3-isopropyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid ethyl ester
A solution of 1-(2,4-dimethoxy-benzyl)-4-hydroxy-3-isopropyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid ethyl ester (HP06, 4.02 g, 10.06 mmol) in phosphorus(V) oxychloride (CAS 100025-87-3, 30 mL, 322 mmol) was stirred at 115° C. for 1 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate, and the reaction mixture was added dropwise to a solution of saturated of sodium hydrogencarbonate till total neutralization of phosphorus(V) oxychloride (pH 8). The aqueous phase was separated and extracted two times with ethyl acetate. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (heptane/EtOAc 100/0 to 75/25) to provide the titled compound.
Illustrative Synthesis of HP20: ethyl 1-tert-butyl-3-cyclobutyl-4-[(trifluoromethanesulfonyl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate




Step 1: diethyl 2-[(1-tert-butyl-3-cyclobutyl-1H-pyrazol-5-yl)amino]but-2-enedioate
In an amber round bottom flask, diethyl acetylenedicarboxylate ([762-21-0], 14.8 mL, 87 mmol) was added to a suspension of AMP94 (15.2 g, 78.8 mmol) in ethanol (200 mL). The reaction mixture was stirred at room temperature for 20 hours, and the mixture was concentrated in vacuo. The crude residue was purified by silica gel column chromatography (heptane/dichloromethane 100/0 to 0/100) to give the titled compound.
Step 2: ethyl 1-tert-butyl-3-cyclobutyl-4-hydroxy-1H-pyrazolo[3,4-b]pyridine-6-carboxylate
In a sealed tube, a suspension of diethyl 2-[(1-tert-butyl-3-cyclobutyl-1H-pyrazol-5-yl)amino]but-2-enedioate (5 g, 13.8 mmol) in Dowtherm® A (5 mL) was heated at 185-190° C. for 24 hours. The reaction mixture was cooled to room temperature and was partitioned between n-heptane and acetonitrile. The acetonitrile phase was separated and evaporated under reduced pressure. The crude sample was purified by silica gel column chromatography (dichloromethane/n-heptane) to give the titled compound.
Step 3: ethyl 1-tert-butyl-3-cyclobutyl-4-[(trifluoromethanesulfonyl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate
Trifluoromethanesulfonic anhydride ([358-23-6], 1.9 mL, 11.3 mmol) was added dropwise to a solution of ethyl 1-tert-butyl-3-cyclobutyl-4-hydroxy-1H-pyrazolo[3,4-b]pyridine-6-carboxylate (2.5 g, 7.89 mmol) and pyridine (1.9 mL, 23.5 mmol) in acetonitrile (80 mL), maintaining the temperature around 20-25° C. The reaction mixture was stirred at RT for 20 hours. Then solid sodium hydrogencarbonate and few milliliters of water were added, and the reaction mixture was concentrated in vacuo. The residue was taken up in dichloromethane and water. The two phases were separated, and the aqueous phase was again extracted with dichloromethane. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (n-heptane/ethyl acetate) to yield the titled compound.
Synthesis of HP12: methyl 4-chloro-1-cyclohexyl-3-isopropyl-pyrazolo[3,4-b]pyridine-6-carboxylate




Step 1: 1-cyclohexyl-3-isopropyl-pyrazolo[3,4-b]pyridine-4,6-diol
A mixture of AMP23 (5.0 g, 24.1 mmol) and diethylmalonate (CAS 105-53, 37.36 mL, 48.2 mmol, 2.0 equiv) was stirred at 190° C. for 2 hours. The reaction mixture was then cooled to RT, and diethyl ether was added. The obtained suspension was filtered; the solid was washed with pentane, and dried in vacuo to give the titled compound.
Step 2: [1-cyclohexyl-3-isopropyl-6-(trifuoromethylsulfonyloxy)pyrazolo[3,4-b]pyridin-4-yl]trifluoromethanesulfonate
Trifluoromethanesulfonic anhydride (CAS 358-23-6, 6.26 mL, 37.2 mmol, 1.75 equiv) was added dropwise at 0° C. to a solution of 1-cyclohexyl-3-isopropyl-pyrazolo[3,4-b]pyridine-4,6-diol (5.85 g, 21.2 mmol) and pyridine (4.3 mL, 53.1 mmol, 2.5 equiv) in acetonitrile (145 mL). The reaction mixture was stirred at RT for 16 hours. Dichloromethane and water were added to the reaction mixture. The two phases were separated, and the organic phase was washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was taken up in toluene and concentrated again in vacuo to give the titled compound.
Step 3: 4, 6-dichloro-1-cyclohexyl-3-isopropyl-pyrazolo[3,4-b]pyridine
A mixture of [1-cyclohexyl-3-isopropyl-6-(trifluoromethylsulfonyloxy)pyrazolo[3,4-b]pyridin-4-yl]trifluoromethanesulfonate (10.86 g, 20.1 mmol) and 4 N HCl in dioxane (50 mL, 200 mmol, 10 equiv) was stirred at 100° C. for 16 hours in a sealed tube. The reaction mixture was cooled to RT and concentrated in vacuo. The residue was purified by chromatography on silica gel (heptane/dichloromethane 100/0 to 80/20) to yield the titled compound.
Step 4: HP12: methyl 4-chloro-1-cyclohexyl-3-isopropyl-pyrazolo[3,4-b]pyridine-6-carboxylate
Triethylamine (1.9 mL, 13.6 mmol, 2.0 equiv) and Pd(dppf)Cl2 (CAS: 72287-26-4, 100 mg, 0.14 mmol, 0.02 equiv) were added to a solution of 4,6-dichloro-1-cyclohexyl-3-isopropyl-pyrazolo[3,4-b]pyridine (2.13 g, 6.82 mmol) in methanol (55 mL). The system was filled at RT with CO (40 psi) and heated at 100° C. for 1 hour. The reaction mixture was cooled down to RT and concentrated in vacuo. The residue was purified by chromatography on silica gel (heptane/ethyl acetate 100/0 to 90/10) to yield the titled compound.
Synthesis of HP14: ethyl 3-cyclobutyl-1-[(2,4-dimethoxyphenyl)methyl]-4-(trifluoromethylsulfonyloxy)pyrazolo[3,4-b]pyridine-6-carboxylate




Trifluoromethanesulfonic anhydride (CAS 358-23-6, 92 HL, 0.56 mmol, 1.45 equiv) was added dropwise at RT to a solution of HP15 (160 mg, 0.39 mmol, 1 equiv) and pyridine (46 μL, 0.58 mmol, 1.5 equiv) in acetonitrile (4 mL). The reaction mixture was stirred at RT for 3 h. Then solid sodium hydrogencarbonate and few milliliters of water were added, and the reaction mixture was concentrated in vacuo. The residue was taken up in dichloromethane and water. The two phases were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (eluent system: heptane/dichloromethane gradient from 100/0 to 0/100) to yield the titled compound.







TABLE VIII







List of halogenated pyrazolopyridine













Int.
Structure
Name
SM
method
MW
Mes





HP01




ethyl 4-chloro- 3-isopropyl-1- (m- tolyl)pyrazolo [3,4-b]pyridine- 6-carboxylate
AMP07
H1 Specific example
357- 359
358- 360


 


HP02




methyl 4- chloro-3- cyclobutyl-1- phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
AMP29
H2 Specific example
341- 343
342- 344


 


HP03




ethyl 4-chloro- 1-[3- (dimethylamino) phenyl]-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
AMP06
H1 (steps 1 to 8) and H1′ (step 9) Specific example
386- 388
387- 389


 


HP04




ethyl 4-chloro- 1-cyclohexyl- 3-isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
AMP23
H1 (steps 1 to 8) and H1′ (step 9)
349- 351
350- 352


 


HP05




methyl 4- chloro-1-(4- fluorophenyl)- 3-isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
AMP13
H2
347- 349
348- 350


 


HP06




ethyl 1-[(2,4- dimethoxyphen- yl)methyl]-4- hydroxy-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
AMP28
H3 (steps 1 & 2 only)
399
400


 


HP07




4-chloro-1-[3- (dimethylamino) phenyl]-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
HP03
J1
358- 360
359- 361


 


HP08




ethyl 4-chloro- 3-isopropyl- 1H- pyrazolo[3,4- b]pyridine-6- carboxylate
AMP28
H3 Specific example
267- 269
268- 270


 


HP09




ethyl 4-chloro- 1-(4- fluorophenyl)- 3-isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP08, 1765- 93-1
I4
361- 363
362- 364


 


HP10




4-chloro-3- cyclobutyl-1- phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
HP02
J1
327- 329
328- 330


 


HP11




4-chloro-1-(4- fluorophenyl)- 3-isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
HP05
J1
333- 335
334- 336


 


HP12




methyl 4- chloro-1- cyclohexyl-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
AMP23
Specific example
335- 337
336- 338


 


HP13




ethyl 4-chloro- 3-methyl-1- phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
1131- 18-6
Specific example
315- 317
316- 318


 


HP14




ethyl 3- cyclobutyl-1- [(2,4- dimethoxyphen- yl)methyl]-4- (trifluoromethyl- sulfonyloxy)py- razolo[3,4- b]pyridine-6- carboxylate
HP15
Specific example
543
544


 


HP15




ethyl 3- cyclobutyl-1- [(2,4- dimethoxyphen- yl)methyl]-4- hydroxy- pyrazolo[3,4- b]pyridine-6- carboxylate
AMP36
H3 (steps 1 & 2 only)1
411
412


 


HP16




4-chloro-3- isopropyl-1- (m- tolyl)pyrazolo [3,4-b]pyridine- 6-carboxylic acid
HP01
J1
329- 331
330- 332


 


HP19




methyl 4- chloro-3- cyclobutyl-1- (4- fluorophenyl)- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
AMP93
Specific example
359- 361
360- 362


 


HP20




ethyl 1-tert- butyl-3- cyclobutyl-4- [(trifluorometh- anesulfonyl) oxy]-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
AMP94
Specific example
449
450


 


HP25




methyl 4- chloro-3- cyclobutyl-1- cyclohexyl- 1H- pyrazolo[3,4- b]pyridine-6- carboxylate
AMP35
Specific example
347
348


 


HP26




4-chloro-3- cyclobutyl-1- (4- fluorophenyl)- 1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
HP19
J1
345
346





1Step 2 performed in Dowtherm TM at 160° C. for 48 h.






Method I1-I34: Synthesis of Esters
Method I1: Cyclization of Alkylidene Pyruvates and Aminopyrazoles




A is either N or CH

A′ is either Re or L1-G3C as described in the Summary

The alkylidene pyruvate (1 to 1.5 equiv) and the aminopyrazole (1 to 1.5 equiv) in acetic acid or DMF are stirred under air at temperatures ranging from RT to reflux for 1 h to several days. Alternatively, the reaction mixture is heated under microwave irradiation at 150° C. for 20 minutes to 2 h followed either by stirring under air in an opened flask at temperatures ranging from RT to 90° C. for 1 h to several days or by removal of the solvent in vacuo, dilution of the residue in ethanol and stirring at reflux for 1 h to several days. Then volatiles are removed in vacuo to afford the titled compound which is used as such or alternatively worked up by dilution with an organic solvent, washed successively with a basic aqueous solution and brine, dried over sodium sulfate, filtered and concentrated in vacuo and used as such or further purified either by precipitation, by preparative HPLC or by flash chromatography on silica gel.
Alternatively, the alkylidene pyruvate (1 equiv) and the aminopyrazole (1 equiv) in N-methylpyrrolidone can be heated at 80 to 100° C. over 8 to 24 hours. Next, the reaction mixture is cooled down to room temperature and a base such as Cs2CO3 (2-6 equiv) is added. The resulting mixture is stirred open to the air until full oxidation is observed.
Illustrative Synthesis of E018: 4-(4-Cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid ethyl ester




The alkylidene pyruvate ALP09 (47.1 g, 150.5 mmol) and the aminopyrazole AMP29 (30 g, 140.7 mmol) were dissolved in acetic acid (240 mL) in an opened round bottom flask equipped with a condenser. The solution was heated at 80° C. for 40 hours and then left cooling down to RT. The mixture was concentrated under reduced pressure, and the crude residue was diluted with DCM (400 mL). The organic phase was washed successively with a saturated aqueous solution of Na2CO3 and a saturated aqueous solution of NaCl, dried over sodium sulfate, filtered and concentrated in vacuo. The crude sample was purified by flash column chromatography eluting with dichloromethane/ethyl acetate. The solid was stirred for 10 minutes in methanol, filtered and dried at 40° C. under reduced pressure to give the titled compound.
Illustrative Synthesis of E425: ethyl 1-cyclohexyl-4-(4-formylphenyl)-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate




A solution of ALP36 (116 mg, 0.5 mmol) and AMP95 (112 mg, 0.5 mmol) in N-methylpyrrolidine (2 mL) was heated at 100° C. for 20 hours in a sealed tube. The volatiles were removed in vacuo, and the residue was purified by flash chromatography on silica gel eluted with ethyl acetate/n-heptane (0/1 to 1/0) to give the titled compound.
Illustrative Synthesis of E503: methyl 4-(4-bromophenyl)-1-cyclohexyl-3-hydroxy-1H-pyrazolo[3,4-b]pyridine-6-carboxylate




5-Amino-1-cyclohexyl-1H-pyrazol-3-ol ([436088-86-7], 5.54 g, 30.5 mmol) and (E)-methyl-4-(4-bromophenyl)-2-oxobut-3-enoate ([608128-34-3], 8.22 g, 30.5 mmol) in NMP (60 mL) were heated overnight at 90° C. Next, the reaction mixture was cooled down to room temperature and Cs2CO3 (30 g, 91.6 mmol) was added. The resulting mixture was stirred open to the air until full oxidation to the titled compound was observed. The obtained solution was used as such for alkylation.
Method I2: Suzuki Coupling
Illustrative Synthesis of E197 and E198: methyl 4-(1-tert-butoxycarbonyl-4-piperidyl)-1-(4-fluorophenyl)-3-isopropyl-pyrazolo[3,4-b]pyridine-6-carboxylate and methyl 4-(1-tert-butoxycarbonyl-3,6-dihydro-2H-pyridin-4-yl)-1-(4-fluorophenyl)-3-isopropyl-pyrazolo[3,4-b]pyridine-6-carboxylate




Step 1: methyl 4-(1-tert-butoxycarbonyl-3,6-dihydro-2H-pyridin-4-yl)-1-(4-fluorophenyl)-3-isopropyl-pyrazolo[3,4-b]pyridine-6-carboxylate E198
A suspension of methyl 4-chloro-1-(4-fluorophenyl)-3-isopropyl-pyrazolo[3,4-b]pyridine-6-carboxylate (HP05, 2.0 g, 5.75 mmol, 1.0 equiv), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (CAS 286961-14-6, 3.6 g, 11.5 mmol, 2.0 equiv), K2CO3 (2.4 g, 17.25 mmol, 3.0 equiv) and Pd(dppf)Cl2 (CAS: 72287-26-4, 939 mg, 1.15 mmol, 0.2 equiv) in anhydrous DMF (15 mL) was degassed with nitrogen at room temperature for 2 minutes. The reaction mixture was heated at reflux overnight. The mixture was cooled to RT, and the mixture was poured into 150 mL of water and diluted with ethyl acetate. The two phases were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The crude residue was purified by silica gel chromatography (heptane/ethyl acetate: 100/0 to 80/20) to give E198.
Step 2: methyl 4-(1-tert-butoxycarbonyl-4-piperidyl)-1-(4-fluorophenyl)-3-isopropyl-pyrazolo[3,4-b]pyridine-6-carboxylate
A suspension of E198 (2.44 g, 4.93 mmol, 1.0 equiv) and platinum(IV) oxide (CAS 1314-15-4, 1.2 g) in AcOH was stirred at RT under hydrogen atmosphere (balloon) overnight. Then the reaction mixture was filtered over Celpure® P65. Solids were washed with ethyl acetate, and the filtrate was concentrated in vacuo. The crude residue was purified by silica gel chromatography (heptane/ethyl acetate: 100/0 to 80/20) to give the title compound.
Method I3: Nucleophilic Substitutions of Amines




A mixture of the chloride or triflate pyrazolopyridine intermediate (1.0 equiv), the amine as free base or hydrochloride salt (from 1 to 10 equiv) and DIPEA (from 1 to 15 equiv) in anhydrous acetonitrile and DMSO in a sealed tube or a round bottom flask is heated at a temperature ranging from 50 to 130° C. for 1 h to several days (up to 8 days). The reaction mixture is cooled to RT, and volatiles are removed in vacuo. The resulting residue is either purified by precipitation or by flash chromatography on silica gel to afford the titled compound or alternatively partitioned between either dichloromethane or ethyl acetate and water. The two phases are then separated, and the aqueous phase is extracted with either ethyl acetate or dichloromethane. The combined organic phases are washed with brine, dried over MgSO4, filtered and concentrated in vacuo and the resulting crude mixture is either used as such or purified by flash chromatography on silica gel to afford the titled compound.
Illustrative Synthesis of E092: methyl 1-(4-fluorophenyl)-3-isopropyl-4-[4-(methoxymethyl)-1-piperidyl]pyrazolo[3,4-b]pyridine-6-carboxylate




A mixture of HP05 (6.71 g, 19.29 mmol, 1.0 equiv), 4-(methoxymethyl)piperidine hydrochloride (CAS 916317-00-5, 6.39 g, 38.58 mmol, 2 equiv) and DIPEA (10.1 mL, 57.88 mmol, 3 equiv) in anhydrous DMSO (65 mL) was heated at 100° C. for 20 h. The reaction mixture was cooled to RT, partitioned between ethyl acetate (300 mL) and a mixture of water and a saturated solution of NaCl 1:1 (300 mL). The two phases were separated, and the aqueous phase was extracted with ethyl acetate (150 mL). The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude mixture was purified by flash chromatography on silica gel eluting with n-heptane/ethyl acetate to afford the titled compound.
Illustrative Synthesis of E356: methyl 3-cyclobutyl-1-(4-fluorophenyl)-4-[4-(4-methoxy-1-piperidyl)-1-piperidyl]pyrazolo[3,4-b]pyridine-6-carboxylate




To a solution of HP19 (8.11 gram, 22.6 mmol) in dry N-methylpyrrolidinone (100 mL) was added 4-methoxy-1,4′-bipiperidine (5.37 gram, 27.1 mmol, AMI10) and diisopropylethylamine (9.42 mL, 54.2 mmol). The reaction mixture was stirred at 100° C. for 24 hours and then cooled down to ambient temperature and diluted with water. A suspension formed upon cooling at 0° C. The suspension was filtered, and the obtained precipitate was washed with water. After drying, the titled compound was obtained.
Illustrative Synthesis of E357: methyl 3-cyclobutyl-1-phenyl-4-{4-[(pyrrolidin-1-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylate




Methyl 4-chloro-3-cyclobutyl-1-phenyl-pyrazolo[3,4-b]pyridine-6-carboxylate (15 g, 43.9 mmol, HP02) and 4-(pyrrolidin-1-ylmethyl)piperidine (13.29 g, 79 mmol) were dissolved in a mixture of N-ethyl-N-isopropylpropan-2-amine (45.9 mL, 263 mmol) and N-methylpyrrolidinone (90 mL). The resulting solution was heated at 100° C. under nitrogen for two hours. After diluting with water (200 mL), the mixture was extracted with tert-butyl methyl ether (3×150 mL). The combined organic fractions were washed with 1 M aqueous NaOH (2×100 mL), water (2×50 mL), and saturated aqueous sodium chloride, then dried over sodium sulfate and concentrated under vacuum to approximately 100 mL followed by the addition of heptanes (200 mL). Volatiles were removed under vacuum, and the resulting thick slurry was stirred overnight at room temperature. The solid was collected by filtration, and then dried to constant weight under vacuum to give 18.39 g of the titled compound. 1H NMR (400 MHz, CDCl3) δ ppm 8.39-8.31 (m, 2H), 7.51 (dd, J=8.6, 7.4 Hz, 2H), 7.40 (s, 1H), 7.31-7.23 (m, 1H), 4.00 (m, 4H), 3.70-3.57 (m, 2H), 2.89 (td, J=12.2, 2.4 Hz, 2H), 2.63 (dq, J=11.7, 9.2 Hz, 2H), 2.56-2.49 (m, 4H), 2.47-2.38 (m, 4H), 2.05 (m, 4H), 1.86-1.78 (m, 4H), 1.73 (m, 1H), 1.53 (qd, J=12.1, 3.7 Hz, 2H); LC/MS (APCI) m/z 474.6 (M+H)+.
Method I4: Chan-Lam Coupling




To a solution of ethyl 1H-pyrazolo[3,4-b]pyridine-6-carboxylate intermediate (1.0 equiv) in dichloromethane at RT is added the aryl boronic acid (2.0 to 3.0 equiv), copper(II) acetate (CAS 142-71-2, 1.5 equiv) and pyridine (4.0 equiv). The reaction mixture is stirred at room temperature under air for 1 h to 48 h. Then the reaction mixture is filtered on a pad of diatomaceous earth. Solids are washed with dichloromethane, and the filtrate is concentrated in vacuo. The resulting residue is purified by flash chromatography on silica gel to afford the titled compound.
Illustrative Synthesis of E111: ethyl 1-(2-fluoro-4-pyridyl)-3-isopropyl-4-(4-methoxy-1-piperidyl)pyrazolo[3,4-b]pyridine-6-carboxylate




To a solution of ethyl 3-isopropyl-4-(4-methoxy-1-piperidyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylate E109 (70 mg, 0.20 mmol, 1.0 equiv) in dichloromethane (2 mL) at RT was added (2-fluoropyridin-4-yl)boronic acid (CAS: 401815-98-3, 56 mg, 0.40 mmol, 2.0 equiv), copper(II) acetate (CAS 142-71-2, 54 mg, 0.30 mmol, 1.5 equiv) and pyridine (64 μL, 0.80 mmol, 4.0 equiv). The reaction mixture was stirred at room temperature under air overnight. The reaction mixture was filtered on a pad of diatomaceous earth. Solids were washed with dichloromethane, and the filtrate was concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (eluent system: heptane/ethyl acetate: 100/0 to 70/30) to give the titled compound.
Method I5: Nucleophilic Substitution




R2 is isopropyl or cyclobutyl

A is CH or N

LG1 and LG2 are independently F, Cl or Br

To a solution of ethyl 3-substituted-1H-pyrazolo[3,4-b]pyridine-6-carboxylate intermediate (1.0 equiv) in anhydrous DMF or THF under nitrogen atmosphere at 0° C. is added sodium hydride (60% in mineral oil, from 1.2 equiv to 1.5 equiv), and the mixture is stirred 5 minutes at 0° C. Then an aromatic halide (2.0 equiv) is added, and the reaction mixture is warmed up to RT and stirred overnight. The reaction mixture is partitioned between water and ethyl acetate and acidified to pH 5 with AcOH. The two phases are separated. The organic phase is washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford the titled compound which is used as such or purified by flash chromatography on silica gel.
Illustrative Synthesis of E133: ethyl 1-(6-bromo-2-pyridyl)-3-isopropyl-4-(4-methoxy-1-piperidyl)pyrazolo[3,4-b]pyridine-6-carboxylate




To a solution of ethyl 3-isopropyl-4-(4-methoxy-1-piperidyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylate E109 (245 mg, 0.71 mmol, 1.0 equiv) in anhydrous DMF (3 mL) under nitrogen atmosphere at 0° C. was added sodium hydride (60% in mineral oil, 34 mg, 0.85 mmol, 1.2 equiv), and the mixture was stirred 5 minutes at 0° C. then 2-bromo-6-fluoropyridine (CAS 144100-07-2, 250 mg, 1.42 mmol, 2.0 equiv) was added, and the reaction mixture was warmed up to RT and stirred overnight. The reaction mixture was partitioned between water and ethyl acetate and acidified to pH 5 with AcOH. The two phases were separated. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford the titled compound which was used as such.
Method I6: Alkylation




To a suspension of ethyl 3-isopropyl-4-[4-(methoxymethyl)-1-piperidyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate E148 (1.0 equiv) in anhydrous DMF under nitrogen atmosphere is added potassium carbonate (1.2 equiv), then alkyl bromide (1.1 equiv). The reaction mixture is stirred at room temperature overnight. Then cesium carbonate (1.2 equiv) and potassium iodide (0.1 equiv) are added, and the reaction mixture is stirred at room temperature for 24 h. The mixture is partitioned between water and ethyl acetate. The aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude mixture is purified by flash chromatography on silica gel to afford the titled compound.
Illustrative Synthesis of E154: ethyl 1-(cyclobutylmethyl)-3-isopropyl-4-[4-(methoxymethyl)-1-piperidyl]pyrazolo[3,4-b]pyridine-6-carboxylate




To a suspension of ethyl 3-isopropyl-4-[4-(methoxymethyl)-1-piperidyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate E148 (100 mg, 0.28 mmol, 1.0 equiv) in anhydrous DMF (2 mL) under nitrogen atmosphere was added potassium carbonate (47 mg, 0.34 mmol, 1.2 equiv) and then (bromomethyl)cyclobutane (CAS: 17247-58-4, 35 μL, 0.31 mmol, 1.1 equiv). The reaction mixture was stirred at room temperature overnight. Then cesium carbonate (111 mg, 0.34 mmol, 1.2 equiv) and potassium iodide (5 mg, 0.028 mmol, 0.1 equiv) were added, and the reaction mixture was stirred at room temperature for 24 h. The mixture was partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude mixture was purified by flash chromatography on silica gel (eluent system: heptane/ethyl acetate gradient from 100/0 to 75/25) to afford the titled compound.
Method I7: Cross-Coupling to Pyrazole
Illustrative Synthesis of E157: ethyl 3-isopropyl-4-[4-(methoxymethyl)-1-piperidyl]-1-(1-methyl-6-oxo-pyridazin-3-yl)pyrazolo[3,4-b]pyridine-6-carboxylate




A suspension of ethyl 3-isopropyl-4-[4-(methoxymethyl)-1-piperidyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate E148 (100 mg, 0.28 mmol, 1.0 equiv) in anhydrous toluene (1 mL) was degassed with nitrogen (bubbling) at room temperature for 5 minutes. Then to this suspension was added 6-bromo-2-methyl-pyridazin-3-one (CAS 1123169-25-4, 58 mg, 0.31 mmol, 1.1 equiv), cesium carbonate (365 mg, 1.12 mmol, 4.0 equiv), Xantphos (CAS 161265-03-8, 16 mg, 0.028 mmol, 0.1 equiv), and palladium(II) acetate (CAS 3375-31-3, 3 mg, 0.014 mmol, 0.05 equiv). The mixture was purged again with nitrogen at RT for 10 minutes, and then the mixture was stirred at reflux overnight. The reaction mixture was cooled down and concentrated in vacuo. The residue was partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude mixture was purified by flash chromatography on silica gel (eluent system: heptane/ethyl acetate gradient from 100/0 to 0/100) to afford the titled compound.
Illustrative Synthesis of E510: methyl 3-cyclobutyl-1-[3-(difluoromethoxy)phenyl]-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate




A nitrogen-purged mixture of tris(dibenzylideneacetone)dipalladium(0) (0.0193 g, 0.021 mmol), and di-tert-butyl(2′,4′,6′-triisopropyl-3,4,5,6-tetramethyl-[1,1′-biphenyl]-2-yl)phosphine (0.0251 g, 0.052 mmol) in toluene (2.2 mL) was stirred for 20 minutes and then added to an nitrogen-purged mixture of methyl 3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate (0.1760 g, 0.441 mmol, E509), 1-bromo-3-(difluoromethoxy)benzene (0.1179 g, 0.529 mmol), and Cs2CO3 (0.2143 g, 0.658 mmol). The mixture was heated to 70° C. overnight, diluted with water, extracted with DCM (3×8 mL), dried (Na2SO4), and concentrated. The residue was chromatographed on silica (30-60% EtOAc/DCM to 4% MeOH/DCM) and re-chromatographed (2.5-4% iPrOH/DCM) to give the titled compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.28-8.16 (m, 2H), 7.58 (t, J=8.2 Hz, 1H), 7.51-7.03 (m, 3H), 3.95 (dq, J=18.1, 9.8, 8.5 Hz, 1H), 3.88 (s, 3H), 3.63-3.48 (m, 6H), 2.91 (t, J=11.9 Hz, 2H), 2.53-2.48 (m, 4H), 2.46-2.28 (m, 2H), 2.12-1.88 (m, 4H), 1.63 (td, J=13.1, 12.6, 6.4 Hz, 2H).
Method I8: Buchwald Coupling




A suspension of ethyl 1-(3-bromophenyl)-3-isopropyl-4-(4-morpholinophenyl)pyrazolo[3,4-b]pyridine-6-carboxylate E001 (1.0 equiv), XPhos Pd G1 (CAS 1028206-56-5, 0.1 equiv) and sodium tert-butoxide (CAS: 865-48-5, 1.3 equiv) in anhydrous toluene is degassed with argon (bubbling) at room temperature for 15 minutes. Amine (1.3 equiv) is added, and the mixture is purged with argon at RT for 2 minutes. The reaction mixture is stirred at 100° C. for 30 minutes to 24 h. The reaction mixture is concentrated in vacuo, and the residue is partitioned between water and dichloromethane and filtered on a pad of Celpure P65®. Solids were washed with dichloromethane and water, and the two phases of the filtrate are separated. The aqueous layer is extracted with dichloromethane. The combined organic phases are washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The titled compound is obtained from the crude mixture either by precipitation or by purification by flash chromatography on silica gel.
Illustrative Synthesis of E002: ethyl 1-[3-(azetidin-1-yl)phenyl]-3-isopropyl-4-(4-morpholinophenyl)pyrazolo[3,4-b]pyridine-6-carboxylate




A suspension of ethyl 1-(3-bromophenyl)-3-isopropyl-4-(4-morpholinophenyl)pyrazolo[3,4-b]pyridine-6-carboxylate E001 (60 mg, 0.115 mmol, 1.0 equiv), XPhos Pd G1 (CAS 1028206-56-5, 9 mg, 0.011 mmol, 0.1 equiv), and sodium tert-butoxide (CAS: 865-48-5, 14 mg, 0.149 mmol, 1.3 equiv) in anhydrous toluene (1.2 mL) was degassed with argon (bubbling) at room temperature for 15 minutes. Azetidine (13 μL, 0.149 mmol, 1.3 equiv) was added, and the mixture was purged with argon at RT for 2 minutes. The reaction mixture was stirred at 100° C. for 1 hour. The reaction mixture was concentrated in vacuo; the residue was partitioned between water and dichloromethane, and then was filtered on a pad of Celpure P65®. Solids were washed with dichloromethane and water, and the two phases of the filtrate were separated. The aqueous layer was extracted with dichloromethane. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluent system: dichloromethane/methanol gradient from 100/0 to 90/10). The obtained solid was suspended in ethanol, filtered, washed with diethyl ether and dried in vacuo to afford the titled compound.
Method I9: Esterification




To the acid (1 equiv) in either ethanol or methanol at RT is added concentrated sulfuric acid (catalytic amount). The reaction mixture is refluxed for 1 h to several days (up to 8 days). Then the reaction mixture is cooled down to RT. The resulting suspension is filtered; the solid is washed with either ethanol or methanol and then dried in vacuo. The crude solid is purified by flash chromatography on silica gel (eluent system: heptane/ethyl acetate) to give the titled compound.
Alternatively, if no suspension is formed when cooling down the reaction mixture, the solvent is removed in vacuo. The resulting residue is taken up in dichloromethane and basified with a saturated solution of NaHCO3. The two phases are separated, and the aqueous phase is extracted with dichloromethane. The combined organic phases are washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford the titled compound which is used as such or further purified by flash chromatography on silica gel.
Illustrative Synthesis of E001 ethyl 1-(3-bromophenyl)-3-isopropyl-4-(4-morpholinophenyl)pyrazolo[3,4-b]pyridine-6-carboxylate




Concentrated sulfuric acid (0.23 mL) was added to a suspension of A242 (2.56 g, 4.9 mmol) in absolute ethanol (64 mL) at RT. The reaction mixture was refluxed for 5 hours. The reaction mixture was cooled down to RT, and the obtained suspension was filtered. The cake was washed with ethanol and dried in vacuo. The solid residue was purified by chromatography on silica gel (heptane/ethyl acetate 100/0 to 70/30) to give the titled compound.
Method I10: Buchwald Coupling on the Aryl Linker




To the amine (from 1.3 to 2 equiv), E010 (1 equiv) and sodium tert-butoxide (CAS: 865-48-5, from 1.3 to 3 equiv) is added degassed anhydrous toluene. The reaction mixture is purged with argon, XPhos Pd G1 (CAS 1028206-56-5, 0.1 equiv) is added, and the mixture is purged again with argon. The reaction mixture is stirred at a temperature ranging from 90° C. to 110° C. for 1 h to 24 h. The reaction mixture is cooled down and filtered on a pad of diatomaceous earth. Solids are washed with organic solvents, and the combined filtrates are concentrated in vacuo. The resulting residue is purified by flash chromatography on silica gel to afford the titled compound.
Illustrative Synthesis of E011: ethyl 4-[4-[3-(dimethylamino)azetidin-1-yl]phenyl]-3-methyl-1-phenyl-pyrazolo[3,4-b]pyridine-6-carboxylate




To N,N-dimethylazetidin-3-amine hydrochloride (CAS: 935670-07-8, 40 mg, 0.194 mmol, 1.3 equiv), E010 (100 mg, 0.23 mmol, 1 equiv) and sodium tert-butoxide (CAS: 865-48-5, 57 mg, 0.598 mmol, 2.6 equiv) was added degassed toluene (2 mL). The reaction mixture was purged with argon, XPhos Pd G1 (CAS 1028206-56-5, 17 mg, 0.023 mmol, 0.1 equiv) was added and the mixture was purged again with argon. The reaction mixture was stirred at 100° C. for 1 hour. The reaction mixture was cooled down and filtered on a pad of diatomaceous earth. Solids were washed with toluene, ethyl acetate and dichloromethane, and the combined filtrates were concentrated in vacuo. The residue was purified by flash chromatography on silica gel (dichloromethane/methanol 98/2) to afford the titled compound.
Method I11: Acylation of Amine
Synthesis of E176: methyl 4-[(1-acetyl-4-piperidyl)methoxy]-1-(4-fluorophenyl)-3-isopropyl-pyrazolo[3,4-b]pyridine-6-carboxylate




To E177 (0.1 g, 0.23 mmol, 1 equiv) in anhydrous dichloromethane (2 mL) at RT was added acetyl chloride (CAS 75-36-5, 19 μL, 0.28 mmol, 1.2 equiv) followed by triethylamine (47 μL, 0.345 mmol, 1.5 equiv). The reaction mixture was stirred at RT for 2 h. The reaction mixture was diluted with dichloromethane and water. The two phases were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (eluent system: heptane/ethyl acetate gradient from 100/0 to 0/100) to afford the titled compound.
Synthesis of E178: methyl 1-(4-fluorophenyl)-3-isopropyl-4-[(1-methoxycarbonyl-4-piperidyl)methoxy]pyrazolo[3,4-b]pyridine-6-carboxylate




To E177 (0.1 g, 0.23 mmol, 1 equiv) in anhydrous dichloromethane (2 mL) at RT was added methyl chloroformate (CAS: 79-22-1, 19 μL, 0.28 mmol, 1.2 equiv) followed by triethylamine (47 μL, 0.345 mmol, 1.5 equiv). The reaction mixture was stirred at RT for 2 h. The reaction mixture was diluted with dichloromethane and water. The two phases were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (eluent system: heptane/ethyl acetate gradient from 100/0 to 50/50) to afford the titled compound.
Synthesis of E042: ethyl 4-(4-acetamidophenyl)-1-(3, 5-difluorophenyl)-3-(1-methoxycarbonylazetidin-3-yl)pyrazolo[3,4-b]pyridine-6-carboxylate




Diisopropylethylamine (0.045 mL, 0.26 mmol, 2.0 equiv) and 4-(dimethylamino)pyridine (CAS 1122-58-3, 3 mg, 0.026, 0.2 equiv) were added to a solution of E043 (65 mg, 0.13 mmol, 1 equiv) in dichloromethane (1 mL) at RT. The reaction mixture was cooled to 0° C. and methyl chloroformate (CAS: 79-22-1, 0.010 mL, 0.13 mmol, 1.0 equiv) was added. The reaction mixture was stirred at RT for 45 min then partitioned between dichloromethane and water. The organic phase was separated, washed with water, dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography (DCM/MeOH: 100/0 to 93/7) to give the titled compound.
Synthesis of E129: methyl 3-cyclobutyl-4-(1-methoxycarbonyl-3,3a,4,6,7,7a-hexahydro-2H-pyrrolo[3, 2-c]pyridin-5-yl)-1-phenyl-pyrazolo[3,4-b]pyridine-6-carboxylate




To E130 (31 mg, 0.073 mmol, 1 equiv) in anhydrous dichloromethane (0.5 mL) at 0° C. was added triethylamine (31 μL, 0.219 mmol, 3 equiv) followed by methyl chloroformate (CAS: 79-22-1, 7 μL, 0.088 mmol, 1.2 equiv). The reaction mixture was stirred at RT for 1.5 h. The reaction mixture was diluted with dichloromethane and water. The two phases were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (eluent system: dichloromethane/methanol, gradient from 100/0 to 98/2) to afford the titled compound.
Synthesis of E132: methyl 4-(1-acetyl-3,3a,4,6,7,7a-hexahydro-2H-pyrrolo[3,2-c]pyridin-5-yl)-3-cyclobutyl-1-phenyl-pyrazolo[3,4-b]pyridine-6-carboxylate




To E130 (31 mg, 0.073 mmol, 1 equiv) in anhydrous dichloromethane (2 mL) at 0° C. was added (31 μL, 0.219 mmol, 3 equiv) followed by acetyl chloride (CAS 75-36-5, 5 μL, 0.088 mmol, 1.2 equiv). The reaction mixture was stirred at RT for 1.5 h. The reaction mixture was diluted with dichloromethane and water. The two phases were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (eluent system: dichloromethane/methanol, gradient from 100/0 to 96/4) to afford the titled compound.
Method I12: Nucleophilic Substitution




To a solution of the intermediate ester (1.0 equiv) in anhydrous DMSO, are added the amine (from 2.0 to 3.0 equiv) and K2CO3 (3.0 equiv). The reaction mixture is stirred at 100° C. overnight. The reaction mixture is cooled down to RT, poured into water and extracted with ethyl acetate. The combined organic layers are washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue is purified by silica gel chromatography to afford the titled compound.
Illustrative Synthesis of E110: ethyl 3-isopropyl-4-(4-methoxy-1-piperidyl)-1-(2-pyrrolidin-1-yl-4-pyridyl)pyrazolo[3,4-b]pyridine-6-carboxylate




To a solution of ethyl 1-(2-fluoro-4-pyridyl)-3-isopropyl-4-(4-methoxy-1-piperidyl)pyrazolo[3,4-b]pyridine-6-carboxylate E111 (50 mg, 0.11 mmol, 1.0 equiv) in anhydrous DMSO (1 mL), were added pyrrolidine (18 μL, 0.22 mmol, 2.0 equiv) and K2CO3 (46 mg, 0.33 mmol, 3.0 equiv). The reaction mixture was stirred at 100° C. overnight. The reaction mixture was cooled down to RT, poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (heptane/ethyl acetate: 100/0 to 40/60) to afford the titled compound.
Method I13: O-Alkylation of the Pyrazole




Intermediate E153 (1.0 equiv), the alkyl iodide (from 3 to 5.7 equiv) and cesium carbonate (from 3 to 5.7 equiv) are charged in a sealed vial. NMP is added, and the vial is sealed. The reaction mixture is stirred at 130° C. for 1 hour. The reaction mixture is cooled down to RT and partitioned between water and ethyl acetate. The phases are separated, and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford the titled compound which is used as such or purified by flash chromatography on silica gel.
Illustrative Synthesis of E152: ethyl 3-[(1-tert-butoxycarbonyl-4-piperidyl)oxy]-4-[6-(4-cyano-1-piperidyl)-3-pyridyl]-1-phenyl-pyrazolo[3,4-b]pyridine-6-carboxylate




Intermediate E153 (110 mg, 0.23 mmol), N-Boc-4-iodo-piperidine (CAS: 301673-14-3, 410 mg, 1.32 mmol, 5.7 equiv) and cesium carbonate (430 mg, 1.32 mmol, 5.7 equiv) were charged in a sealed vial. NMP (2.9 mL) was added, and the vial was sealed. The reaction mixture was stirred at 130° C. for 1 hour. The reaction mixture was cooled down to RT and partitioned between water and ethyl acetate. The phases were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (heptane/ethyl acetate: gradient from 100/0 to 2:1) to give the titled compound.
Method I14: Mitsunobu Reaction




Diisopropyl azodicarboxylate (CAS: 2446-83-5, 0.606 mL, 3.075 mmol, 1.5 equiv) is added dropwise to a stirred solution of the intermediate phenol HP (1 equiv), tetrahydropyran-4-methanol (CAS: 14774-37-9, from 1.5 to 2.0 equiv) and triphenylphosphine (CAS: 603-35-0, 1.5 equiv) in tetrahydrofuran under nitrogen atmosphere. The reaction mixture is stirred at RT for 1 to 3 h. The solvent is removed under reduced pressure, and the resulting crude sample is purified by flash column chromatography on silica gel (eluent system: heptane/ethyl acetate) to yield the titled compound.
Illustrative Synthesis of E183 ethyl 1-[(2,4-dimethoxyphenyl)methyl]-3-isopropyl-4-(tetrahydropyran-4-ylmethoxy)pyrazolo[3,4-b]pyridine-6-carboxylate




Diisopropyl azodicarboxylate (CAS: 2446-83-5, 0.606 mL, 3.075 mmol, 1.5 equiv) was added dropwise to a stirred solution of HP06 (820 mg, 2.05 mmol), tetrahydropyran-4-methanol (CAS: 14774-37-9, 477 mg, 4.1 mmol, 2.0 equiv) and triphenylphosphine (CAS: 603-35-0, 806 mg, 3.075 mmol, 1.5 equiv) in tetrahydrofuran (20 mL) under nitrogen atmosphere. The reaction mixture was stirred at RT for 1 hour. The volatiles were removed under reduced pressure, and the crude sample was purified by flash column chromatography on silica gel eluting with n-heptane/ethyl acetate from 90/10 to 1/1 to yield the titled compound.
Method I15: Dimethoxybenzyl Group Removal




Trifluoroacetic acid or a mixture of dichloromethane and trifluoroacetic acid is added to the (2,4-dimethoxyphenyl)methyl]pyrazolo[3,4-b]pyridine compound. The reaction mixture is stirred at RT for several hours. Then the titled compound is isolated by precipitation in diethyl ether directly from the reaction mixture or after removal of volatiles and is used as such or is taken up in dichloromethane and basified with a saturated solution of sodium hydrogencarbonate. The phases are separated and the aqueous phase is extracted with dichloromethane. The combined organic phases are washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford the titled compound which is used as such or further purified by silica gel chromatography.
Alternatively the reaction mixture is concentrated in vacuo. The residue is taken up in dichloromethane and basified with a saturated solution of sodium hydrogencarbonate. The phases are separated and the aqueous phase is extracted with dichloromethane. The combined organic phases are washed with brine, dried over MgSO4, filtered and concentrated in vacuo which was used as such or purified by precipitation or by flash chromatography on silica gel.
Illustrative Synthesis of Compound E055: ethyl 3-isopropyl-4-(4-morpholinophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylate




Trifluoroacetic acid (4.24 mL, 55.4 mmol, 71 equiv) was added to compound E056 (424 mg, 0.78 mmol). The reaction mixture was stirred at RT for 3 hours. Diethyl ether (20 mL) was added to the reaction mixture which was vigorously stirred for 5 minutes. The resulting suspension was filtered, and the cake was washed with diethyl ether. The solid was partitioned between dichloromethane and a saturated solution of sodium hydrogencarbonate and vigorously stirred. The suspension was filtered, and the solids were washed with dichloromethane. The two phases of the filtrate were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over MgSO4, filtered and concentrated in vacuo to yield the titled compound which was used without further purification.
Method I16: Ullmann Coupling
Synthesis of E171: ethyl 3-cyclobutyl-1-(4-fluorophenyl)-4-(tetrahydropyran-4-ylmethoxy)pyrazolo[3,4-b]pyridine-6-carboxylate




A degassed solution of trans-N,N′-dimethyl-1,2-cyclohexane (CAS: 67579-81-1, 0.002 mL, 0.01 mmol, 0.15 equiv) and 1-fluoro-4-iodobenzene (CAS: 352-34-1, 0.007 mL, 0.06 mmol, 0.7 equiv) in toluene (2 mL) was added to a mixture of E172 (30 mg, 0.08 mmol), K3PO4 (35 mg, 0.167 mmol, 2.0 equiv) and CuI (1 mg, 0.005 mmol, 0.07 equiv). The vial was sealed and the reaction mixture was stirred at 110° C. for 16 hours. The reaction mixture was cooled down to RT and partitioned between water and ethyl acetate. The organic phase was separated, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (dichloromethane/heptane/ethyl acetate: 100/0/0 to 0/70/30) to give the titled compound.
Method I17: O-Alkylation of Pyrazole
Synthesis of Compound E090: isopropyl 3-isopropoxy-4-(4-morpholinophenyl)-1-phenyl-pyrazolo[3,4-b]pyridine-6-carboxylate




To a solution of A256 (330 mg, 0.79 mmol) and 2-iodopropane (CAS 75-30-9, 0.19 mL, 1.90 mmol, 2.4 equiv) in anhydrous NMP (4 mL) was added cesium carbonate (775 mg, 2.38 mmol, 3.0 equiv), and the reaction mixture was stirred at 130° C. for 16 hours. The reaction mixture was cooled down to RT and partitioned between dichloromethane and a saturated solution of sodium hydrogencarbonate. The organic phase was separated, washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate: 80/20 to 70/30) to give the titled compound.
Synthesis of Intermediate E504: methyl 4-(4-bromophenyl)-1-cyclohexyl-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate




To a solution containing methyl 4-(4-bromophenyl)-1-cyclohexyl-3-hydroxy-1H-pyrazolo[3,4-b]pyridine-6-carboxylate (30.5 mmol, E503) was added isopropyl bromide ([75-26-3], 5.73 mL, 61.1 mmol) and cesium carbonate (2.70 g, 8.28 mmol), and the resulting mixture stirred under N2 at 60° C. for 1 hour. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with brine (2×) and concentrated. The obtained residue was purified by column chromatography using a petroleum ether/EtOAc gradient (95/5 till 90/10) to afford the titled compound.
Synthesis of Intermediate E505: methyl 4-(4-bromophenyl)-3-(cyclobutyloxy)-1-cyclohexyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylate




To a solution containing methyl 4-(4-bromophenyl)-1-cyclohexyl-3-hydroxy-1H-pyrazolo[3,4-b]pyridine-6-carboxylate (5.52 mmol, E503) was added cyclobutyl bromide ([4399-47-7], 1.04 mL, 11.0 mmol) and cesium carbonate (5.40 g, 11.0 mmol), and the resulting mixture stirred under N2 at 60° C. for 1 hour. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with brine (2×) and concentrated. The obtained residue was purified by column chromatography using a petroleum ether/EtOAc gradient (95/5 till 90/10) to afford the titled compound.
Method I18: General Method for Reductive Amination




A suspension of ketone (1 eq), amine (1.5 to 3 eq) and triethylamine (1 to 2 eq) in dichloromethane is stirred at RT for 5 minutes. Acetic acid (1 to 2 eq) is added, and the stirring at RT is continued for 30 minutes. Sodium triacetoxyborohydride (1 to 3 eq) is then added, and the stirring is continued for 20 hours. The reaction mixture is diluted with dichloromethane and washed with a saturated aqueous solution of NaHCO3. The organic phase is separated, dried over sodium sulfate and concentrated under reduced pressure. The crude sample is used as such or purified by flash column chromatography.
Illustrative Synthesis of E354: methyl 3-cyclobutyl-1-(4-fluorophenyl)-4-{4-[2-(methoxymethyl)morpholin-4-yl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylate




A suspension of E353 (0.1 g, 0.24 mmol), 2-(methoxymethyl)morpholine ([156121-15-2], 63 mg, 0.47 mmol) and triethylamine (33 μL, 0.24 mmol) in dichloromethane (2 mL) was stirred at RT for 5 minutes. Acetic acid (21 μL, 0.35 mmol) was added, and the stirring at RT was continued for 30 minutes. Sodium triacetoxyborohydride (76 mg, 0.35 mmol) was then added, and the stirring was continued for 20 hours. The reaction mixture was diluted with dichloromethane (3 mL) and washed with a saturated aqueous solution of NaHCO3 (2 mL). The organic phase was separated using a phase separator and concentrated in vacuo to give the titled compound.
Method I19: General Method for the Reductive Removal of Benzyloxycarbonyl




A solution of the benzyloxycarbonyl-protected amine (1 eq) in methanol is flushed with N2. Next, 10% Pd/C (0.1 eq) is added and the mixture is put under hydrogen pressure with a balloon. After stirring overnight at ambient temperature, the mixture is filtered through diatomaceous earth, and the filtrate is concentrated. The residue is used as such or purified by flash column chromatography.
Method I23: General Method for Oxidation




Dess Martin's periodinane (1 to 2 eq) is added at RT to a stirred solution of alcohol (1 eq) in dichloromethane. After 0.5 to 2 hours, the reaction mixture is diluted with dichloromethane. A solution of 20% Na2S2O3 in water and a saturated aqueous solution of NaHCO3 (1:1) is added and the stirring is continued for 30 minutes. The organic phase is separated, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the titled compound. The compound can be used as such or purified by flash column chromatography.
Synthesis of Compound E353: Methyl 3-cyclobutyl-1-(4-fluorophenyl)-4-(4-oxopiperidin-1-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylate




Dess-Martin periodinane (4 g, 9.4 mmol) was added at RT to a stirred solution of E352 (3.6 g, 8.6 mmol) in dichloromethane (40 mL). After 30 minutes, the reaction mixture was diluted with dichloromethane (50 mL). A solution of 20% aqueous Na2S2O3 20% and a saturated aqueous solution of NaHCO3 (1:1, 50 mL) were added, and the stirring was continued for 30 minutes. The organic phase was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the titled compound.
Method I24: Coupling of Amines




EDC.HCl ([25952-538], 1.2 equiv) is added at RT to a stirring solution of carboxylic acid (1 equiv), amine (4 equiv) and 4-(dimethylamino) pyridine ([1122-58-3], 2 equiv) in dichloromethane. The reaction mixture is stirred at RT for 20 hours. The solvent is evaporated under reduced pressure. The residue is purified flash column chromatography eluting with ethyl acetate/n-heptane and/or DCM/MeOH to yield the desired compound.
Illustrative Synthesis of E439: ethyl 4-{4-[5-(tert-butoxycarbonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carbonyl]phenyl}-1-cyclohexyl-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate




EDC.HCl ([25952-538], 18 mg, 74 μmol) was added at RT to a stirred solution of E438 (30 mg, 62 μmol), tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate ([141449-85-6], 52 mg, 248 μmol) and 4-(dimethylamino) pyridine ([1122-58-3], 17 mg, 124 μmol) in dichloromethane (5 mL). The reaction mixture was stirred at RT for 20 hours. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with ethyl acetate/n-heptane to yield the titled compound.
Illustrative Synthesis of E441: ethyl 1-cyclohexyl-4-{4-[3-(dimethylamino)azetidine-1-carbonyl]phenyl}-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate




EDC.HCl ([25952-538], 24 mg, 125 μmol) was added at RT to a stirred solution of E438 (40 mg, 89 μmol), N,N-dimethylazetidin-3-amine hydrochloride ([935670-07-8], 49 mg, 358 μmol), triethylamine (50 μL, 358 μmol) and 4-(dimethylamino)pyridine ([1122-58-3], 24 mg, 196 μmol) in dichloromethane (15 mL). The reaction mixture was stirred at RT for 20 hours. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with ethyl acetate/DCM/MeOH (100/0/0 to 0/90/10) to yield the titled compound.
Method I25: tert-Butoxycarbonyl (Boc) Deprotection




To a solution of the Boc-protected amine (1 eq) in dichloromethane at 0° C., TFA (76-05-1, 5-20 eq) is added. The resulting mixture is stirred at room temperature until deprotection is complete. The mixture can be worked up by diluting the reaction mixture with DCM followed by washing with a saturated aqueous NaHCO3 solution. The organic fraction is dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the titled compound. Alternatively, the reaction mixture can be concentrated under reduced pressure, and the crude titled compound can be used as such without further purification.
Illustrative Synthesis of Compound E043: ethyl 4-(4-acetamidophenyl)-3-(azetidin-3-yl)-1-(3,5-difluorophenyl)pyrazolo[3,4-b]pyridine-6-carboxylate




Trifluoroacetic acid (1.0 mL, 13.0 mmol, 33 equiv) was added at 0° C. to a solution of E044 (230 mg, 0.39 mmol) in dichloromethane (5.0 mL). The reaction mixture was stirred at RT for 1 hour. The reaction mixture was partitioned between dichloromethane and a saturated solution of sodium hydrogencarbonate. The organic phase was separated, dried over Na2SO4, filtered and concentrated to give the titled compound.
Illustrative Synthesis of Compound E130: methyl 4-(1,2,3,3a,4,6,7,7a-octahydropyrrolo[3,2-c]pyridin-5-yl)-3-cyclobutyl-1-phenyl-pyrazolo[3,4-b]pyridine-6-carboxylate




A solution of 4 M HCl in dioxane (0.245 mL, 0.98 mmol, 4.0 equiv) was added at RT to a solution of E131 (130 mg, 0.24 mmol) in dioxane (2.0 mL). The reaction mixture was stirred at RT for 16 hours. Additional 4 M HCl in dioxane (0.1 mL, 0.4 mmol, 1.7 equiv) was added, and the reaction mixture was stirred at RT for 48 hours. The reaction mixture was concentrated in vacuo and partitioned between dichloromethane and a saturated solution of sodium hydrogencarbonate. The organic phase was separated, dried over Na2SO4, filtered and concentrated in vacuo to give the titled compound.
Method I26: Reductive Amination to Install a Cyclopropyl Group




The amine (1 eq) is mixed with (1-ethoxycyclopropoxy)trimethylsilane ([27374-25-0], 2 eq), AcOH (1.6 eq) and NaBH3CN (1.5 eq) in a mixture of THF/MeOH (1/1). The resulting mixture is stirred overnight at 50° C. After cooling the mixture down to room temperature, the reaction is quenched by the addition of water. Next, 1 M NaOH solution is added, and the mixture is stirred for another 15 minutes. After dilution with DCM, the organic layer is separated, dried and concentrated to give the titled compound.
Illustrative Synthesis of Compound E465: methyl 3-cyclobutyl-4-[4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl]-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylate




Methyl 3-cyclobutyl-1-(4-fluorophenyl)-4-[4-(piperazin-1-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate (200 mg, 0.41 mmol, E498) was mixed with (1-ethoxycyclopropoxy)trimethylsilane ([27374-25-0], 163 μL, 0.81 mmol), AcOH (26 μL, 0.65 mmol) and sodium cyanoborohydride ([25895-60-7], 38 mg, 0.61 mmol) in a mixture of THF/MeOH (1/1, 1 mL). The resulting mixture was stirred overnight at 50° C. After cooling the mixture down to room temperature, the reaction was quenched by the addition of water. Next, 1 M NaOH solution was added, and the mixture was stirred for another 15 minutes. After dilution with DCM, the organic layer was separated, dried and concentrated to give the titled compound.
Method I27: Alkylation Amine




The amine (1 eq) is mixed with 1-bromo-2-methoxyethane ([6482-24-2], 1.1 eq) and K2CO3 (2 eq) in MeCN. The resulting mixture is heated at reflux overnight at 50° C. After cooling down, the mixture is used as such in the next step.
Method I28: Amino-Carbonylation




A is CH or N
In a Parr reactor, the arylbromide (1 eq) is mixed with an amine (2 eq), Et3N (4 eq) and Xantphos Pd G3 (0.03 eq) in dioxane. A CO pressure of 5 bars is applied and the mixture is heated at 100° C. overnight. Concentration gives a residue that is re-dissolved in DCM. Extraction with water gives an organic phase that is concentrated to give a residue that is used as such in the next step.
Illustrative Synthesis of Compound E474: methyl 1-cyclohexyl-4-[4-(4-methylpiperazine-1-carbonyl)phenyl]-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate




A Parr reactor was loaded with E504 (0.50 mmol, 250 mg), 1-methylpiperazine dihydrochloride ([34352-59-5], 1.0 mmol, 173 mg) and [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate] (0.015 mmol, 14 mg). The reactor was evacuated and back-filled with N2, Et3N (4.0 equiv, 2.0 mmol, 279 μL) and 1,4-dioxane (dry, 8 mL/mmol, 4 mL) were added, and the reaction mixture was heated to 100° C. under a CO atmosphere (5 bar) overnight. The reaction mixture was concentrated in vacuo, and the residue was partitioned between H2O and dichloromethane. The organic phase was dried and concentrated in vacuo to give the titled compound which was used as such in the next step.
Method I29: Alternative Buchwald Coupling on the Aryl Linker




A tube is loaded with the arylbromide (1 eq). The amine (1.2 eq) is added together with (RuPhos) palladium(II) phenethylamine chloride (1:1 MTBE solvate, 0.1 eq), NaOtBu (1.2 eq) in dioxane. The resulting suspension is put under a N2 atmosphere and stirred at 100° C. Next, the mixture is diluted with water and acidified with a 1 N citric acid solution till pH 3-4. Extraction with DCM gives the crude product that is either used as such or purified by chromatography. During this method, it is possible that partial hydrolysis of the ester to the corresponding acid occurs.
Illustrative Synthesis of Compound E502: methyl 1-cyclohexyl-4-[4-(4-methylpiperazin-1-yl)phenyl]-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate




A tube was loaded with the E504 (100 mg, 0.21 mmol). 1-Methylpiperazine ([109-01-3], 28 μL, 0.25 mmol) was added together with (RuPhos) palladium(II) phenethylamine chloride (1:1 MTBE solvate, 17 mg, 0.02 mmol), and NaOtBu (25 mg, 0.25 mmol) in dioxane (1 mL). The resulting suspension was put under a N2 atmosphere and stirred at 100° C. Next, the mixture was diluted with water and acidified with a 1 N citric acid solution till pH 3-4. Extraction with DCM gave the titled compound that was used as such. Partial hydrolysis of the ester to the corresponding acid was observed.
Method I30: Alternative Reductive Amination




A solution of the amine (1 eq), the ketone (2 eq) and AcOH (1.5 eq) in DCM is cooled to 0° C. Next, sodium triacetoxyborohydride ([56553-60-7], 2 eq) is added portionwise, and the reaction is stirred overnight at ambient temperature. Subsequently, the mixture is diluted with saturated NaHCO3 solution and extracted with DCM. The organic phase is concentrated to give the alkylated amine that is used as such or purified by chromatography.
Illustrative Example of Compound E469: methyl 3-cyclobutyl-1-(4-fluorophenyl)-4-[9-(oxetan-3-yl)-3, 9-diazaspiro[5.5]undecan-3-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate




A solution of the methyl 3-cyclobutyl-4-(3,9-diazaspiro[5.5]undecan-3-yl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylate (200 mg, 0.42 mmol, E500), 3-oxetanone ([6704-31-0], 54 μL, 0.84 mmol) and AcOH (36 μL) in DCM (3 mL) was cooled at 0° C. Next, sodium triacetoxyborohydride ([56553-60-7], 178 mg, 0.84 mmol) was added portion wise and the reaction was stirred overnight at ambient temperature. Subsequently, the mixture was diluted with sat. NaHCO3 solution and extracted with DCM. The organic phase was evaporated to give the titled compound.
Method I31: Carbamate Synthesis




To a solution of the amine (1 eq) in DCM is added trimethylamine (2 eq) and then methyl chloroformate ([79-22-1], 2 eq). The mixture is stirred at RT overnight. Next, the reaction mixture is diluted with saturated NaHCO3 solution and extracted with DCM. After concentration, the carbamate is obtained that is used as such or purified by chromatography.
Illustrative Example of Compound E486: methyl 3-cyclobutyl-1-(4-fluorophenyl)-4-{4-[4-(methoxycrbonyl)piperazin-1-yl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylate




To a solution of the E498 (118 mg, 0.239 mmol) in DCM (1 mL) was added triethylamine (67 μL, 0.478 mmol) and then methyl chloroformate (37 μL, 0.478 mmol). The mixture was stirred at RT overnight. Next, the reaction mixture was diluted with saturated NaHCO3 solution and extracted with DCM. After concentration, the titled compound was obtained that was used as such.
Method I32: Amide Synthesis Using Acetyl Chloride




To a solution of the amine (1 eq) in DCM is added trimethylamine (2 eq) and then acetyl chloride ([75-36-5], 2 eq). The mixture is stirred at RT overnight. Next, the reaction mixture is diluted with saturated NaHCO3 solution extracted with DCM. After concentration, the amide is obtained that is used as such or purified by chromatography.
Illustrative Example of Compound E487: methyl 4-[4-(4-acetylpiperazin-1-yl)piperidin-1-yl]-3-cyclobutyl-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylate




To a solution of the E498 (118 mg, 0.239 mmol) in DCM (1 mL) was added triethylamine (67 μL, 0.478 mmol) and then acetyl chloride ([75-36-5], 0.478 mmol). The mixture was stirred at RT overnight. Next, the reaction was diluted with saturated NaHCO3 solution and extracted with DCM. After concentration, the titled compound was obtained that was used as such.
Method I34: Reductive Amination on Aldehydes




A is —O—C1-C6 alkyl or —NHS(O)2R5 
A suspension of amine hydrochloride or free base (1 to 2 equiv) and triethylamine (from 1 to 2 equiv) in 1,2-dichloroethane is stirred at RT for 10 minutes. Aldehyde (1 equiv), sodium triacetoxyborohydride (2 equiv), and acetic acid (0.6 to 4 equiv) are successively added, and the stirring at RT is continued for 20 hours. Starting reagents can be added until full conversion is observed. The reaction mixture is diluted with DCM, washed with a saturated aqueous solution of NaHCO3 and/or a saturated aqueous solution of NH4Cl and a phosphate buffer (pH 6.2). The organic phase is dried over sodium sulfate and concentrated under reduced pressure. The residue is used as such or purified by flash column chromatography to yield the reductively aminated compound.
Illustrative Synthesis of E426: ethyl 1-cyclohexyl-4-(4-{[3-(dimethylamino)azetidin-1-yl]methyl}phenyl)-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate




A suspension of 3-(dimethylamino)azetidine dihydrochloride ([124668-49-1], 17 mg, 124 μmol) and triethylamine (35 μL, 248 μmol) in 1,2-dichloroethane (2 mL) was stirred at RT for 10 minutes. Aldehyde E425 (54 mg, 124 μmol), sodium triacetoxyborohydride (53 mg, 248 mol), and acetic acid (29 μL, 496 μmol) were successively added, and the stirring at RT was continued for 20 hours. The reaction mixture was diluted with DCM and washed with a saturated aqueous solution of NaHCO3. The organic phase was separated, dried over sodium sulfate and concentrated under reduced pressure. The residue was used as such or purified by flash column chromatography eluted with ethyl acetate/n-heptane to yield the titled compound.
Synthesis of E199: methyl 4-(4-azidophenyl)-1-[3-(dimethylamino)phenyl]-3-isopropyl-pyrazolo[3,4-b]pyridine-6-carboxylate




Intermediate E074 (0.5 g, 1.013 mmol, 1.0 equiv) and sodium azide (CAS 26628-22-8, 132 mg, 2.026 mmol, 2 equiv) were put in a sealed vial. A 2:1 mixture of ethanol and water (2 mL) was added, and the vial was purged with nitrogen. Then copper(I) iodide (CAS 7681-65-4, 20 mg, 0.101 mmol, 0.1 equiv), sodium ascorbate (CAS 134-03-2, 11 mg, 0.051 mmol, 0.05 equiv) and N,N′-dimethylethylenediamine (CAS 110-70-3, 45 μL, 0.405 mmol, 0.2 equiv) were added, and the vial was sealed. The reaction mixture was heated under microwave irradiation at 80° C. for 45 minutes. Volatiles were removed in vacuo. The resulting aqueous residue was diluted with ethyl acetate. The two phases were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford the titled compound which was used as such.
Synthesis of E390: ethyl 3-cyclobutyl-1-[2-(3,6-dihydro-2H-pyran-4-yl)pyridin-4-yl]-4-[4-(methoxymethyl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate and E391: ethyl 3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-1-[2-(oxan-4-yl)pyridin-4-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate




Step 1: E390: ethyl 3-cyclobutyl-1-[2-(3,6-dihydro-2H-pyran-4-yl)pyridin-4-yl]-4-[4-(methoxymethyl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate
In a sealed tube, a suspension of E389 (110 mg, 0.23 mmol), 3,6-dihydro-2H-pyran-4-boronic pinacol ester (72 mg, 0.34 mmol), K3PO4 (146 mg, 0.69 mmol) and Pd(Amphos)Cl2 ([887919-35-9], 16 mg, 23 μmol) in dioxane (3 mL) and water (0.5 mL) was degassed with N2 at room temperature for 2 minutes. The reaction mixture was heated at 100° C. for 3 hours. The mixture was cooled to RT and then concentrated under reduced pressure. The crude sample was purified by flash column chromatography eluted with ethyl acetate/n-heptane to give the titled compound E390.
Step 2: E391: ethyl 3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-1-[2-(oxan-4-yl)pyridin-4-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate
A suspension of E390 (60 mg, 0.11 mmol) and palladium hydroxide on carbon (20 mg) in ethanol was hydrogenated for 6 hours. The reaction mixture was filtered over Celpure® and washed with ethyl acetate. The filtrate was concentrated in vacuo, and the residue was purified by silica gel chromatography eluted with ethyl acetate/n-heptane to give the titled compound E391.
Synthesis of E393: ethyl 3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate




Trifluoromethanesulfonic acid (860 μL, 10 mmol) was added dropwise at RT to a solution of E392 (1 g, 2 mmol) in dichloromethane (10 mL). The reaction mixture was stirred for 4 hours and poured into a mixture of saturated aqueous NaHCO3 and water (1:1, 10 mL). The aqueous phase was extracted twice with dichloromethane/isopropanol (95/5, 20 mL). The combined organic phases were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the titled compound as a colorless solid.
Synthesis of E402: ethyl 3-cyclobutyl-1-(2-hydroxypyridin-4-yl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate




A suspension of E401 (75 mg, 0.12 mmol) and palladium hydroxide on carbon (10 mg) in THF was hydrogenated for 20 hours. The reaction mixture was filtered over Celpure® that was washed with dichloromethane/methanol. The filtrate was concentrated in vacuo to give the titled compound E402.
Synthesis of E407: ethyl 3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-[2-(oxan-4-yl)pyridin-4-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate




Step 1: ethyl 3-cyclobutyl-1-[2-(3,6-dihydro-2H-pyran-4-yl)pyridin-4-yl]-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate
In a sealed tube, a suspension of E406 (110 mg, 0.21 mmol), 3,6-dihydro-2H-pyran-4-boronic pinacol ester (72 mg, 0.34 mmol), K3PO4 (146 mg, 0.69 mmol) and Pd(Amphos)Cl2 ([887919-35-9], 16 mg, 23 μmol) in dioxane (3 mL) and water (0.5 mL) was degassed with N2 at room temperature for 2 minutes. The reaction mixture was heated at 100° C. for 20 hours. The mixture was cooled to RT, and the mixture was concentrated under reduced pressure. The crude sample was purified by flash column chromatography eluted with ethyl acetate/n-heptane to give the titled compound.
Step 2: ethyl 3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-[2-(oxan-4-yl)pyridin-4-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate
A suspension of ethyl 3-cyclobutyl-1-[2-(3,6-dihydro-2H-pyran-4-yl)pyridin-4-yl]-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate (54 mg, 0.94 mmol) and palladium hydroxide on carbon (15 mg) in ethanol/THF (1:1, 10 mL) was hydrogenated for 6 hours. The reaction mixture was filtered over Celpure® that was washed with ethyl acetate, and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography eluted with ethyl acetate/n-heptane to give the titled compound, E407.
Synthesis of E413: methyl 3-cyclobutyl-1-(4-fluorophenyl)-4-(piperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylate




Step 1: methyl 4-[1-(tert-butoxycarbonyl)-, 2,3,6-tetrahydropyridin-4-yl]-3-cyclobutyl-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylate
A suspension of methyl 4-chloro-3-cyclobutyl-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylate (HP19, 2.0 g, 5.75 mmol, 1.0 equiv), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (CAS 286961-14-6, 3.6 g, 11.5 mmol, 2.0 equiv), K2CO3 (2.4 g, 17.25 mmol, 3.0 equiv) and Pd(dppf)Cl2 (CAS: 72287-26-4, 939 mg, 1.15 mmol, 0.2 equiv) in anhydrous DMF (15 mL) was degassed with nitrogen at room temperature for 2 minutes. The reaction mixture was refluxed for 20 hours. The mixture was cooled to RT, poured into 150 mL of iced water and diluted with ethyl acetate. The two phases were separated, and the aqueous phase was extracted again with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography (heptane/ethyl acetate: 100/0 to 80/20) to give the titled compound.
Step 2: methyl 4-[1-(tert-butoxycarbonyl)piperidin-4-yl]-3-cyclobutyl-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylate
A suspension of compound from Step 1 (2.44 g, 4.93 mmol, 1.0 equiv) and platinum (IV) oxide (CAS 1314-15-4, 1.2 g) in acetic acid (240 mL) was stirred at RT under a hydrogen atmosphere (balloon) for 20 hours. The reaction mixture was filtered over Celpure® P65. Solids were washed with ethyl acetate, and the filtrate was concentrated in vacuo. The crude residue was purified by silica gel chromatography (heptane/ethyl acetate: 100/0 to 80/20) to give the title compound.
Step 3: methyl 3-cyclobutyl-1-(4-fluorophenyl)-4-(piperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylate
Methyl 4-[1-(tert-butoxycarbonyl)piperidin-4-yl]-3-cyclobutyl-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylate (2.75 g, 5.4 mmol, 1 equiv) was dissolved in 4 M HCl in dioxane (40 mL, 162.2 mmol, 30 equiv), and the solution was stirred at RT for 2 hours. The solvent was concentrated under reduced pressure. The residue was dissolved in a minimum of methanol and poured into diethyl ether (500 mL). The precipitate was filtered, washed with diethyl ether and dried at 40° C. under reduced pressure to give the titled compound, E413.
Synthesis of E430: methyl 3-cyclobutyl-4-(1,4-dioxaspiro[4,5]dec-7-en-8-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylate




In a sealed tube, a suspension of HP02 (1 g, 2.92 mmol), 1,4-dioxa-spiro[4,5]dec-7-en-8-boronic acid, pinacol ester ([680596-79-6], 1.01 g, 3.8 mmol), K3PO4 (1.86 g, 8.77 mmol), Pd(OAc)2 ([3375-31-3], 330 mg, 0.14 mmol), and SPhos ([657408-07-6], 150 mg, 0.365 mmol) in toluene (22 mL) and water (6 mL) was degassed with N2 at room temperature for 5 minutes. The reaction mixture was stirred at RT for 2 hours. Additional Pd(OAc)2 ([3375-31-3], 330 mg, 0.14 mmol) and SPhos ([657408-07-6], 150 mg, 0.365 mmol) were added. The stirring at RT was continued for 20 hours. Pd(OAc)2 ([3375-31-3], 165 mg, 0.07 mmol) and SPhos ([657408-07-6], 75 mg, 0.18 mmol) were again added, and the reaction mixture was heated at 100° C. for 1 hour. The reaction mixture was cooled to RT, diluted with ethyl acetate and filtered. The filtrate was washed successively with water and a saturated aqueous solution of NaCl. The organic phase was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by flash column chromatography on silica gel eluting with ethyl acetate/n-heptane to give the titled compound.
Synthesis of E431: methyl 3-cyclobutyl-4-(1,4-dioxaspiro[4,5]decan-8-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylate




A suspension of E430 (823 mg, 1.85 mmol) and palladium hydroxide on carbon ([12135-22-7], 280 mg) in THF/MeOH (25 mL, 2/1) was hydrogenated for 20 hours. The reaction mixture was filtered over Celpure® which was washed with DCM. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography eluting with ethyl acetate/n-heptane to give the titled compound E431.
Synthesis of E432: methyl 3-cyclobutyl-1-[(3E,5Z)-hepta-1, 3, 5-trien-4-yl]-4-(4-oxocyclohexyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylate




The ester, E431 (732 mg, 1.64 mmol), was dissolved in DCM and TFA (2.2 mL, 3 volumes) was added dropwise at RT. The solution was stirred for 48 hours and then diluted with DCM. The mixture was washed with a saturated aqueous solution of NaHCO3. The organic phase was separated, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with ethyl acetate/n-heptane to give the titled compound E432.
Synthesis of E438: 4-{1-cyclohexyl-6-(ethoxycarbonyl)-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridin-4-yl}benzoic acid




A mixture of aldehyde E425 (27 mg, 62 μmol), sulfamic acid ([226-18-8], 17 mg, 168 μmol), and sodium chlorite ([7758-19-2], 17 mg, 188 μmol) in THF/water (3.3 mL, 10/1) was stirred at RT for 1 hour. The reaction mixture was diluted with DCM (20 mL) and washed with water (20 mL). The organic phase was dried over sodium sulfate, filtered and evaporated under reduced pressure. The titled compound was used as such in the next step.
Synthesis of E444: ethyl 1-cyclohexyl-4-{4-[(8-methyl-2-oxa-5,8-diazaspiro[3.5]nonan-5-yl)methyl]phenyl}-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate




Iodomethane (3 μL, 48 μmol) was added at RT to a stirred suspension of E443 (22 mg, 40 μmol) and cesium carbonate (33 mg, 100 μmol) in DMF (2 mL). The reaction mixture was stirred for 20 hours. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with ethyl acetate/DCM/MeOH (100/0/0 to 0/90/10) to give the titled compound.
Synthesis of E445: ethyl 4-[4-(4-cyano-1-methylpiperidin-4-yl)phenyl]-1-cyclohexyl-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate




Step 1: ethyl 4-{4-[1-(tert-butoxycarbonyl)-4-cyanopiperidin-4-yl]phenyl}-1-cyclohexyl-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate
A solution of ALP38 (305 mg, 0.74 mmol) and AMP95 (575 mg, 0.77 mmol) in N-methylpyrrolidine (4 mL) was heated at 110° C. for 24 hours in an opened vessel. The reaction mixture was cooled to RT, and the mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic phase was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/n-heptane to give the titled compound.
Step 2: ethyl 4-[4-(4-cyanopiperidin-4-yl)phenyl]-1-cyclohexyl-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate
Trifluoroacetic acid (1 mL) was added to a solution of the tert-butoxycarbonyl protected compound from Step 1 (230 mg, 0.37 mmol) in DCM (10 mL). The solution was stirred at RT for 2 hours. The reaction mixture was diluted with toluene (5 mL) and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate, water, and a phosphate buffer solution (pH 6.2). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate/n-heptane to give the titled compound.
Step 3: ethyl 4-[4-(4-cyano-1-methylpiperidin-4-yl)phenyl]-1-cyclohexyl-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate
Iodomethane (2 μL, 32 μmol) was added at RT to a stirred suspension of the compound from Step 2 (15 mg, 29 μmol) and cesium carbonate (33 mg, 100 μmol) in DMF (2 mL). The reaction mixture was stirred for 2 hours. The reaction mixture was partitioned between water and DCM. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with ethyl acetate/DCM/MeOH (100/0/0 to 0/90/10) to give the titled compound.
Synthesis of E509: methyl 3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate




Step 1: 4-[1-(2,6-dichloropyridin-4-yl)piperidin-4-yl]morpholine
N-Ethyl-N-isopropylpropan-2-amine (22.91 mL, 132 mmol) was added to a suspension of 2,4,6-trichloropyridine (12 g, 65.8 mmol) and 4-(piperidin-4-yl)morpholine (13.44 g, 79 mmol) in acetonitrile (120 mL). The reaction mixture was heated to 60° C. and stirred for 16 hours. Upon cooling to room temperature, the precipitate was collected by filtration. The crude solid was then precipitated from EtOAc to give the titled compound. 1H NMR (400 MHz, CDCl3) δ ppm 6.59 (s, 2H), 3.89-3.79 (m, 2H), 3.77-3.69 (m, 4H), 2.96 (ddd, J=13.3, 11.8, 2.8 Hz, 2H), 2.60-2.52 (m, 4H), 2.45 (tt, J=10.8, 3.7 Hz, 1H), 1.95 (ddd, J=12.9, 3.9, 1.9 Hz, 2H), 1.61-1.48 (m, 2H); MS (APCI+) m/z 316.2 (M+H)+.
Step 2: cyclobutyl{2, 6-dichloro-4-[4-(morpholin-4-yl)piperidin-1-yl]pyridin-3-yl}methanone
n-Butyllithium (19.2 mL, 26.9 mmol) was added in 5 mL portions to a stirred solution of 4-[1-(2,6-dichloropyridin-4-yl)piperidin-4-yl]morpholine (7.95 g, 25.1 mmol) in THF (160 mL) at −78° C. After stirring at this temperature for 1.5 hours, cyclobutanecarbonyl chloride (1.42 g, 11.9 mmol) was added rapidly, and the reaction mixture was stirred for 10 minutes. To obtain higher conversion, sequential additions of n-butyllithium and cyclobutanecarbonyl chloride were performed in the same manner. Addition 1: n-butyllithium (13.0 mL, 18.2 mmol) and cyclobutanecarbonyl chloride (0.97 g, 8.1 mmol); Addition 2: n-butyllithium (9.2 mL, 12.9 mmol) and cyclobutanecarbonyl chloride (0.68 g, 5.6 mmol); Addition 3: n-butyllithium (6.9 mL, 9.7 mmol) and cyclobutanecarbonyl chloride (0.51 g, 4.2 mmol); Addition 4: n-butyllithium (5.7 mL, 8.0 mmol) and cyclobutanecarbonyl chloride (0.41 g, 3.4 mmol). Upon completion of the last addition, the excess n-butyl lithium was quenched with water (200 mL), and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic fractions were washed with brine (100 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (0-5% 95/5 MeOH/30% aqueous NH3 in DCM) to give the titled compound. 1H NMR (400 MHz, CDCl3) δ ppm 6.76 (s, 1H), 3.80-3.65 (m, 5H), 3.50-3.40 (m, 2H), 2.98-2.76 (m, 2H), 2.62-2.50 (m, 4H), 2.50-2.37 (m, 2H), 2.29 (tt, J=11.0, 3.8 Hz, 1H), 2.22-2.08 (m, 2H), 2.08-1.93 (m, 2H), 1.93-1.83 (m, 2H), 1.52 (dddd, J=14.8, 12.8, 7.5, 3.8 Hz, 2H); MS (APCI+) m/z 398.2 (M+H)+.
Step 3: 6-chloro-3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine
Hydrazine (35% in water, 3.10 mL, 33.9 mmol) was added to cyclobutyl{2,6-dichloro-4-[4-(morpholin-4-yl)piperidin-1-yl]pyridin-3-yl}methanone (4.5 g, 11.30 mmol) in EtOH (32 mL). The reaction mixture was heated to reflux for 14 hours. Upon cooling to −5° C., the precipitate was isolated by filtration. The filter cake was rinsed with cold EtOH to give the titled compound. 1H NMR (400 MHz, CDCl3) δ ppm 10.21 (br s, 1H), 6.45 (s, 1H), 3.94-3.76 (m, 5H), 3.63 (d, J=12.4 Hz, 2H), 2.84 (td, J=12.4, 2.3 Hz, 2H), 2.71-2.59 (m, 4H), 2.58-2.44 (m, 2H), 2.44-2.31 (m, 3H), 2.14-1.97 (m, 4H), 1.85-1.70 (m, 2H); MS (APCI+) m/z 376.2 (M+H)+.
Step 4: methyl 3-cyclobutyl-4-(4-morpholinopiperidin-1-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylate
Into a 600 mL Parr reactor was charged 6-chloro-3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine (3.4 g, 9.05 mmol), followed by THF (170 mL) and MeOH (170 mL). 1,1′-Bis(diphenylphosphino)ferrocene-palladium (II) dichloride dichloromethane complex (0.739 g, 0.905 mmol), and triethylamine (2.52 mL, 18.09 mmol) were added to give a suspension. The reaction vessel was purged with argon followed by CO, pressurized to 100 psig with CO, and heated to 80° C. After 8 hours, the reaction mixture was cooled to room temperature, diluted with CH2Cl2 (800 mL), and filtered. The filtrate was concentrated in vacuo, and the residue was dissolved in CH2Cl2 (800 mL). The organic mixture was washed with saturated aqueous NaHCO3 (300 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was slurried in EtOAc to give the titled compound. 1H NMR (400 MHz, CDCl3) δ ppm 10.98 (br s, 1H), 7.37 (s, 1H), 4.08 (s, 3H), 3.96 (p, J=8.4 Hz, 1H), 3.83-3.76 (m, 4H), 3.70 (d, J=12.3 Hz, 2H), 2.92 (t, J=11.8 Hz, 2H), 2.66 (t, J=4.7 Hz, 4H), 2.55 (dq, J=11.3, 9.0 Hz, 2H), 2.44-2.31 (m, 3H), 2.15-2.00 (m, 4H), 1.88-1.74 (m, 2H); MS (APCI+) m/z 400.3 (M+H)+.
Synthesis of E511: methyl 1-(4-fluorophenyl)-4-(4-methoxy[1,4′-bipiperidin]-1′-yl)-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate







Step 1: 1-(4-fluorophenyl)-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-4,6-diol
In a sealed tube, a suspension of AMP96 (215 mg, 0.91 mmol) and diethyl malonate ([105-53-3], 418 μL, 2.75 mmol) in Dowtherm® A was heated at 200° C. 4 hours. The reaction mixture was cooled down to 70-80° C. and poured onto a stirring solution of n-heptane (200 mL). The precipitate was collected by filtration, washed with n-heptane and dried at 40° C. under reduced pressure to give the titled compound.
Step 2: 1-(4-fluorophenyl)-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-4,6-diyl bis(trifluoromethanesulfonate)
Trifluoromethanesulfonic anhydride ([358-23-6], 302 μL, 1.8 mmol) was added dropwise to a solution of 1-(4-fluorophenyl)-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-4,6-diol (270 mg, 0.9 mmol, Step 1) and pyridine (220 μL, 2.25 mmol) in acetonitrile (5 mL), maintaining the temperature around 20-25° C. The reaction mixture was stirred at RT for 20 hours. The reaction mixture was diluted with DCM and extracted twice with a saturated aqueous solution of NaHCO3. The organic phase was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (n-heptane/ethyl acetate, 1/0 to 0/1) to yield the titled compound.
Step 3: 1-(4-fluorophenyl)-4-(4-methoxy[1,4′-bipiperidin]-1′-yl)-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridin-6-yl trifluoromethanesulfonate
A mixture of 1-(4-fluorophenyl)-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-4,6-diyl bis(trifluoromethanesulfonate) (29 mg, 50 μmol, Step 2), 4-methoxy-1-piperidin-4-ylpiperidine hydrochloride ([930603-98-8], 14 mg, 50 μmol) and DIPEA (35 μL, 200 μmol) in anhydrous DMSO (1 mL) was heated at 100° C. for 2 hours. The reaction mixture was cooled to RT and partitioned between ethyl acetate (50 mL) and water (30 mL). The organic phase was separated, dried over MgSO4, filtered and concentrated in vacuo. The crude mixture was purified by flash chromatography on silica gel eluting with n-heptane/ethyl acetate (1/0 to 0/1) and ethyl acetate/(DCM/MeOH, 9/1) (1/0 to 0/1) to afford the titled compound.
Step 4: methyl 1-(4-fluorophenyl)-4-(4-methoxy[1,4′-bipiperidin]-1′-yl)-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate
A pressured vessel was charged with 1-(4-fluorophenyl)-4-(4-methoxy[1,4′-bipiperidin]-1′-yl)-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridin-6-yl trifluoromethanesulfonate (145 mg, 240 μmol, Step 3), Pd(dppf)Cl2.DCM ([95464-05-4], 4 mg, 4.8 μmol), and triethylamine (66 μL, 500 μmol) in MeOH (5 mL). The system was loaded with CO (6 bars) and heated at 100° C. for 1 hour. The vessel was cooled down to RT, and the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with a mixture of ethyl acetate/(DCM/MeOH, 9/1) (1/0 to 0/1) to give the titled compound.
Synthesis of AMI01: 4-(methoxymethyl)piperidin-4-ol hydrochloride




Step 1: 4-Hydroxy-4-methoxymethyl-piperidine-1-carboxylic acid tert-butyl ester
A suspension of tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (CAS: 147804-30-6, 200 mg, 0.94 mmol) and sodium methoxide (61 mg, 1.13 mmol) in methanol (2 mL) was placed in a sealed tube and was heated at 100° C. for 20 hours. The reaction mixture was cooled to RT, acidified with acetic acid to pH 5-6, diluted with DCM and washed with water. The organic phase was separated using a phase separator and concentrated in vacuo. The titled compound was used as such in the next step without any further purification.
Step 2: 4-Methoxymethyl-piperidin-4-ol hydrochloride
4-Hydroxy-4-methoxymethyl-piperidine-1-carboxylic acid tert-butyl ester (206 mg, 0.84 mmol) was dissolved in dioxane (2 mL). 4 M HCl in dioxane (1.05 mL, 4.2 mmol) was added, and the solution was stirred at RT for 20 hours. The volatiles were removed under reduced pressure. The titled compound was used as such in the next step without any further purification.
Synthesis of AMI02: 4-[(1,1-dioxo-1, 4-thiazinan-4-yl)methyl]piperidin-4-ol hydrochloride




Step 1: tert-butyl 4-[(1,1-dioxo-1, 4-thiazinan-4-yl)methyl]-4-hydroxy-piperidine-1-carboxylate
A solution of tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (CAS: 147804-30-6, 150 mg, 0.7 mmol) and thiomorpholine 1,1-dioxide (CAS: 39093-93-1, 380 mg, 2.8 mmol) in ethanol (2 mL) was placed in a sealed tube and was heated at 75° C. for 20 hours. The reaction mixture was cooled to RT, diluted with DCM and washed with water. The organic phase was separated using a phase separator and concentrated in vacuo. The titled compound was obtained by flash column chromatography eluting with DCM/MeOH.
Step 2: 4-[(1,1-dioxo-1, 4-thiazinan-4-yl)methyl]piperidin-4-ol hydrochloride
tert-Butyl 4-[(1,1-dioxo-1,4-thiazinan-4-yl)methyl]-4-hydroxy-piperidine-1-carboxylate (215 mg, 0.62 mmol) was dissolved in dioxane (2 mL). 4 M HCl in dioxane (0.89 mL, 3.6 mmol) was added, and the solution was stirred at RT for 20 hours. The volatiles were removed under reduced pressure. The titled compound was used as such in the next step without any further purification.
Synthesis of AMI03: (2S)-2-fluoro-N,N-dimethyl-2-(4-piperidyl)ethanamine hydrochloride




Step 1: (S)-tert-butyl 4-(1-fluoro-2-oxoethyl)piperidine-1-carboxylate
To a suspension of N-fluoro-N-(phenylsulfonyl)benzenesulfonamide ((CAS 133745-75-2, 347 g, 1100 mmol) and (5R)-(+)-2,2,3-trimethyl-5-benzyl-4-imidazolidinone dichloroacetic acid (CAS 857303-87-8, 76 g, 220 mmol) in THF and isopropyl alcohol at −20° C. was added a solution of tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (250 g, 1100 mmol, CAS: 142374-19-4) in THF. The mixture was stirred at 10° C. for 16 h, diluted with hexane at −78° C. and filtered through silica, washed with hexane, then with saturated aqueous NaHCO3, dried, filtered, and concentrated to give (S)-tert-butyl 4-(1-fluoro-2-oxoethyl)piperidine-1-carboxylate.
Step 2: (S)-tert-butyl 4-(1-fluoro-2-hydroxyethyl)piperidine-1-carboxylate
A solution of (S)-tert-butyl 4-(1-fluoro-2-oxoethyl)piperidine-1-carboxylate (10 g, 40.8 mmol) in dichloromethane (280 mL) and ethanol (220 mL) was stirred at 10° C. Then, sodium borohydride (CAS 16940-66-2, 4.0 g, 105.7 mmol, 2.6 equiv) was added. The mixture was stirred at 10° C. for 1 hour, was diluted with water and extracted with dichloromethane. The organic layer was dried, filtered and concentrated, and the residue was purified by chromatography on silica gel (petroleum ether:ethyl acetate) to give (S)-tert-butyl 4-(1-fluoro-2-hydroxyethyl)piperidine-1-carboxylate.
Step 3: (S)-tert-butyl 4-(2-(benzylamino)-1-fluoroethyl)piperidine-1-carboxylate
Trifluoromethanesulfonic anhydride (CAS 358-23-6, 5.70 g, 20.22 mmol, 1.0 equiv) was added to a solution of (S)-tert-butyl 4-(1-fluoro-2-hydroxyethyl)piperidine-1-carboxylate (5 g, 20.22 mmol) and 2,6-dimethylpyridine (CAS 108-48-5, 2.166 g, 20.22 mmol, 1.0 equiv) in dichloromethane at 0° C. The mixture was stirred at 0° C. for 0.5 h. A separated round bottom flask was charged with benzylamine (2.166 g, 20.22 mmol, 1.0 equiv) in dichloromethane at 0° C. The solution of the triflate was then added slowly at 0° C. The reaction mixture was stirred at 25° C. for 12 hours, quenched with a saturated aqueous solution of sodium hydrogencarbonate, and extracted with dichloromethane. The organic fraction was concentrated. The residue was purified on silica gel chromatography, eluting with acetone/dichloromethane to give (S)-tert-butyl 4-(2-(benzylamino)-1-fluoroethyl)piperidine-1-carboxylate.
Step 4: (S)-tert-butyl 4-(2-amino-1-fluoroethyl)piperidine-1-carboxylate
To a solution of (S)-tert-butyl 4-(2-(benzylamino)-1-fluoroethyl)piperidine-1-carboxylate (4.5 g, 13.38 mmol) in methanol was added Pd/C, then the solution was stirred at 35° C. under hydrogen atmosphere (45 psi) for 12 hours. The mixture was filtered and concentrated to give (S)-tert-butyl 4-(2-amino-1-fluoroethyl)piperidine-1-carboxylate.
Step 5: (S)-tert-butyl 4-(2-(dimethylamino)-1-fluoroethyl)piperidine-1-carboxylate
To a mixture of (S)-tert-butyl 4-(2-amino-1-fluoroethyl)piperidine-1-carboxylate (3.0 g, 12.18 mmol) in methanol was added paraformaldehyde (CAS 30525-89-4, 1.828 g, 60.9 mmol, 5.0 equiv) followed by three drops of acetic acid. The reaction mixture stirred for 1 hour. Then sodium cyanoborohydride (CAS 25895-60-7, 1.148 g, 18.27 mmol, 1.5 equiv) was added, and the mixture was stirred for 12 hours. The reaction mixture was filtered and concentrated, and the residue was purified by column chromatography on silica gel (DCM/MeOH) to afford (S)-tert-butyl 4-(2-(dimethylamino)-1-fluoroethyl)piperidine-1-carboxylate
Step 6: (S)-2-fluoro-N,N-dimethyl-2-(piperidin-4-yl)ethanamine hydrochloride
To a solution of (S)-tert-butyl 4-(2-(dimethylamino)-1-fluoroethyl)piperidine-1-carboxylate (2 g, 7.29 mmol) in MeOH was added 4 N hydrogen chloride in methanol (10 mL, 40 mmol, 5.5 equiv), and the mixture was stirred at RT for 2 hours. Then the solution was concentrated to give (S)-2-fluoro-N,N-dimethyl-2-(piperidin-4-yl)ethanamine hydrochloride.
Synthesis of AMI04: 4-(ethoxymethyl)-4-fluoro-piperidine




Step 1: 1-tert-butyl 4-ethyl 4-fluoropiperidine-1,4-dicarboxylate
In a 100 mL round-bottomed flask was combined 1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate (1 g, 3.89 mmol) and THF (10 mL). The solution was cooled to −78° C., and sodium hexamethyldisilazide (6 mL of 1 M THF solution, 6.00 mmol) was added slowly via syringe. After 60 min, N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (2 g, 6.34 mmol) in THF (3 mL) was added. After 2 h, dichloromethane/water (1:1, 40 mL) was added. The aqueous layer was extracted with dichloromethane, and the combined organic fractions were dried over Na2SO4, filtered, and concentrated in vacuo.
Step 2: tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate
A solution of 1-tert-butyl 4-ethyl 4-fluoropiperidine-1,4-dicarboxylate (1.5 g, 5.45 mmol) in THF (5 mL) was cooled to 0° C., and then 1 M LiAlH4 in THF (3.81 mL, 3.81 mmol) was added dropwise. The reaction mixture was warmed up to RT and stirred for 2 h. Water (0.9 mL) was added to the reaction mixture dropwise followed by 2 N NaOH (0.3 mL). The mixture was stirred for another 30 minutes, and then solid removed by filtration through diatomaceous earth and washed with EtOAc. The filtrate was washed with brine, dried over Na2SO4, and concentrated from acetonitrile under vacuum several time to remove the water to afford tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate.
Step 3: tert-butyl 4-(ethoxymethyl)-4-fluoropiperidine-1-carboxylate
tert-Butyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate (30 g, 129 mmol) was first treated with sodium hydride (6.17 g, 154 mmol) DMF (500 mL), and then iodoethane (24.07 g, 154 mmol) was added at room temperature. The reaction mixture was stirred at 25° C. for 12 h. The mixture was washed with H2O and extracted with EtOAc, and then the combined organic phases were washed with H2O, and brine. The organic fraction was dried Na2SO4, filtered and concentrated to give tert-butyl 4-(ethoxymethyl)-4-fluoropiperidine-1-carboxylate (26.9 g, 103 mmol, 80% purity).
Step 4: 4-(ethoxymethyl)-4-fluoro-piperidine
A mixture of tert-butyl 4-(ethoxymethyl)-4-fluoropiperidine-1-carboxylate 26.9 g, 103 mmol) in ethyl acetate (200 mL) was made acidic by addition of HCl in ethyl acetate solution at 0° C. Then the mixture was allowed to warm to 15° C. and stirred at 15° C. for 3 h. The reaction mixture was concentrated under vacuum to yield 4-(ethoxymethyl)-4-fluoropiperidine as a hydrochloride salt (15.27 g, 95 mmol, 92% yield).
Synthesis of AMI05: 4-fluoro-4-(2-methoxyethoxymethyl)piperidine




Step 1: tert-butyl 4-fluoro-4-((2-methoxyethoxy)methyl)piperidine-1-carboxylate
To a mixture of tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate (30 g, 129 mmol, prepared as described in the synthesis of AMI04) in DMF (400 mL) was added sodium hydride (6.43 g, 161 mmol) at 0° C. After 15 minutes, 1-bromo-2-methoxyethane (35.7 g, 257 mmol) was added at 0° C., and the mixture was stirred at 25° C. for 12 h. The mixture was quenched with 200 mL of aqueous NH4Cl at 5° C. The organic layer was separated, washed with water and brine, dried over Na2SO4, and concentrated. After column chromatography on silica gel (petroleum ether/EtOAc=10:1 to petroleum ether/EtOAc=2:1), tert-butyl 4-fluoro-4-((2-methoxyethoxy)methyl)piperidine-1-carboxylate (20.5 g, 70.4 mmol, 54.% yield) was obtained.
Step 2: 4-fluoro-4-(2-methoxyethoxymethyl)piperidine
A solution of tert-butyl 4-fluoro-4-((2-methoxyethoxy)methyl)piperidine-1-carboxylate (20 g, 68.6 mmol) in 200 mL EtOAc was made acidic with HCl in EtOAc at room temperature. After TLC on silica gel (petroleum ether/EtOAc=1:1) showed that the reaction was complete, the mixture was concentrated to afford the titled compound as a hydrochloride salt (15 g, 65.9 mmol, 96% yield).
Synthesis of AMI07: 4-fluoro-4-(methoxymethyl)piperidine




Step 1: tert-butyl 4-fluoro-4-(methoxymethyl)piperidine-1-carboxylate
To a mixture of tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate (30 g, 129 mmol, prepared as described in the synthesis of AMI04) and NaH (3.09 g, 129 mmol) in THF (500 mL) was added iodomethane (41.9 g, 295 mmol) at room temperature, and then the mixture was stirred at 25° C. for 12 h, The reaction mixture was diluted with water and extracted with EtOAc. The combined organic phases were washed with water and brine. The organic fraction was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified on a silica gel column eluted with petroleum ether/EtOAc=2:1 to give tert-butyl 4-fluoro-4-(methoxymethyl)piperidine-1-carboxylate (25 g, 101 mmol, 79% yield).
Step 2: 4-fluoro-4-(methoxymethyl)piperidine
A mixture of tert-butyl 4-fluoro-4-(methoxymethyl)piperidine-1-carboxylate (25 g, 101 mmol) in EtOAc (300 mL) was made acidic with HCl in EtOAc at 0° C., and the mixture was allowed to warm to 15° C. and stirred at 15° C. for 3 h. The reaction mixture was concentrated under vacuum to yield the titled compound as a hydrochloride salt (13 g, 70.8 mmol, 70.0% yield).
Synthesis of AMI08: 3-fluoro-3-(2-methoxyethoxymethyl)piperidine




Step 1: tert-butyl 3-fluoro-3-((2-methoxyethoxy)methyl)piperidine-1-carboxylate
To a mixture of tert-butyl 3-fluoro-3-(hydroxymethyl)piperidine-1-carboxylate (25 g, 107 mmol) in THF (300 mL) was added NaH (2.57 g, 107 mmol) at 0° C. After 15 minutes, 1-bromo-2-methoxyethane (29.8 g, 214 mmol) was added at 0° C. The mixture was stirred at 25° C. for 12 h, and then the reaction was quenched by the addition of saturated aqueous NH4Cl and extracted with EtOAc. The combined organic phases were washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuum. The residue was added to a silica gel column eluted with hexanes:ethyl acetate (2:1) to give tert-butyl 3-fluoro-3-((2-methoxyethoxy)methyl)piperidine-1-carboxylate (22 g, 76 mmol, 70.5% yield).
Step 2: 3-fluoro-3-(2-methoxyethoxymethyl)piperidine
A mixture of tert-butyl 3-fluoro-3-((2-methoxyethoxy)methyl)piperidine-1-carboxylate (25 g, 86 mmol) in EtOAc (200 mL) was made acidic with HCl in EtOAc at 0° C. The mixture was allowed to warm to 15° C. and stirred at 15° C. for 3 h. The reaction mixture was concentrated under vacuum to the titled compound as a hydrochloride salt (15 g, 65.9 mmol, 77% yield).
Synthesis of AMI09: 2-(4-hydroxy-4-piperidyl)acetonitrile hydrochloride




Step 1: tert-butyl 4-(cyanomethyl)-4-hydroxy-piperidine-1-carboxylate
A flame-dried round bottom flask was cooled down to RT under argon. A solution of 1 M LiHMDS in THF (1.51 mL, 3.02 mmol, 2.0 equiv) was introduced into the flask and cooled down to −78° C. (acetone/dry ice bath). Dry MeCN (157 μL, 3.02 mmol, 2.0 equiv) in anhydrous THF (5 mL) was then added dropwise under argon, and the reaction mixture was stirred for 45 minutes at −78° C. At this point, a solution of 1-(tert-butoxycarbonyl)-4-piperidone (300 mg, 1.51 mmol, 1.0 equiv) in dry THF (5 mL) was added dropwise, and the reaction mixture was stirred at −78° C. for 1 h. The reaction mixture was quenched with an aqueous saturated solution of ammonium chloride and diluted with ethyl acetate. The two phases were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford tert-butyl 4-(cyanomethyl)-4-hydroxypiperidine-1-carboxylate which was used as such in the next step.
Step 2: 2-(4-hydroxy-4-piperidyl)acetonitrile hydrochloride
tert-Butyl 4-(cyanomethyl)-4-hydroxypiperidine-1-carboxylate (226 mg, 0.94 mmol, 1 equiv) was dissolved in dioxane (2.5 mL). 4 M HCl in dioxane (1.41 mL, 1.88 mmol, 6 equiv) was added, and the solution was stirred at RT for 5 days. The reaction mixture was concentrated under reduced pressure. The titled compound was used as such without any further purification.
Synthesis of AMI10: 4-methoxy-1,4′-bipiperidine




Step 1: benzyl 4-methoxy-[1,4′-bipiperidine]-1′-carboxylate
To a solution of benzyl 4-oxopiperidine-1-carboxylate ([19099-93-5], 40 gram, 171 mmol) and 4-methoxypiperidine ([4045-24-3], 24.6 gram) in dichloromethane (800 mL) was added acetic acid (10.8 mL, 189 mmol) and sodium triacetoxyborohydride (54.5 gram, 257 mmol). The mixture was stirred at 0° C. for 120 minutes. Next, the mixture was washed with a saturated aqueous K2CO3 solution. The organic phase was separated and concentrated to give a residue that was purified by chromatography on silica gel using a gradient elution with CH2Cl2 to CH2Cl2/CH3OH (100/0 to 97/2.5) to give the titled compound.
Step 2: 4-methoxy-1,4′-bipiperidine
Benzyl 4-methoxy-[1,4′-bipiperidine]-1′-carboxylate (23 gram, 69 mmol) was dissolved in CH3OH (350 mL). The solution was flushed with N2 and 10% Pd/C (7.3 gram, 6.9 mmol) was added. After applying a balloon with H2, the mixture was stirred at ambient temperature overnight. Next, the mixture was filtered through diatomaceous earth, and the resulting filtrate was concentrated to give the titled compound.
Synthesis of AMI11: 1-piperidin-1-ium-4-ylpiperidine-4-carbonitrile chloride




Step 1: tert-butyl 4-(4-cyano-1-piperidyl)piperidine-1-carboxylate
A suspension of 4-cyanopiperidine ([4395-98-6], 500 mg, 4.5 mmol), tert-butyl 4-oxopiperidine-1-carboxylate ([79099-07-3], 900 mg, 4.5 mmol) and AcOH (0.27 mL) in DCM (66 mL) was cooled at 0° C. Next, sodium triacetoxyborohydride ([56553-60-7], 955 mg, 4.5 mmol) was added portion wise. After overnight stirring, the reaction was diluted with 60 mL of water together with a 1 N citric acid solution to bring down the pH till 3-4. The organic layer was separated and discarded. Next, the aqueous layer was brought to neutral pH with a saturated aqueous NaHCO3 solution. After extraction with DCM, the organic phase was concentrated to give the titled compound.
Step 2: 1-piperidin-1-ium-4-ylpiperidine-4-carbonitrile chloride
tert-Butyl 4-(4-cyano-1-piperidyl)piperidine-1-carboxylate (662 mg, 2.26 mmol) was dissolved in DCM and trifluoroacetic acid ([76-05-1], 0.93 mL) was added. After overnight stirring, the mixture was concentrated to dryness. The obtained residue was suspended in 4 N HCl in dioxane. The addition of ethanol gave a suspension which was filtered to give the titled compound as a precipitate.
Synthesis of ALC02: (2R)-2-fluoro-2-tetrahydropyran-4-yl-ethanol




Step 1: (2R)-2-fluoro-2-tetrahydropyran-4-yl-acetaldehyde
To a mixture of (R)-5-benzyl-2,2,3-trimethylimidazolidin-4-one dichloroacetic acid salt (CAS 857303-87-8, 2.71 g, 7.80 mmol, 0.2 equiv) and N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (CAS 133745-75-2, 12.30 g, 39 mmol, 1.0 equiv) in THF (200 mL) and isopropyl alcohol (25 mL) was slowly added at −20° C. a solution 2-(tetrahydro-2H-pyran-4-yl)acetaldehyde (5 g, 39 mmol, CAS 65626-23-5) in THF (25 mL). The mixture was stirred at −20° C. for 12 hours, then diluted with hexane (800 mL) cooled to −78° C. and filtered through silica, washed with hexane. The filtrate was concentrated to give (R)-2-fluoro-2-(tetrahydro-2H-pyran-4-yl)acetaldehyde.
Step 2: (2R)-2-fluoro-2-tetrahydropyran-4-yl-ethanol
To a solution of (R)-2-fluoro-2-(tetrahydro-2H-pyran-4-yl)acetaldehyde (4 g, 27.4 mmol) in dichloromethane (48 mL) and ethanol (40 mL) was added sodium borohydride (CAS 16940-66-2, 2.59 g, 68.4 mmol, 2.5 equiv). The mixture was stirred at 25° C. for 12 hours, then diluted with water and extracted with dichloromethane. The organic layer was dried, filtered, concentrated and purified by chromatography (petroleum ether, ethylate) to give (2R)-2-fluoro-2-tetrahydropyran-4-yl-ethanol.
Synthesis of ALC03: 1-[4-fluoro-4-(hydroxymethyl)-1-piperidyl]ethanone




Step 1: tert-butyl 4-(bromomethyl)-4-fluoropiperidine-1-carboxylate
To a mixture of tert-butyl 4-methylenepiperidine-1-carboxylate (159635-49-1, 50 g, 253 mmol) and triethylamine trihydrofluoride (102 g, 634 mmol) in dichloromethane (1 L) was added 1-bromopyrrolidine-2,5-dione (67.7 g, 380 mmol) at 0° C. After 15 min, stirring was continued at 20° C. for 3 h. Then the mixture was poured into ice-water, neutralized with aqueous 28% ammonia and extracted with dichloromethane. The combined extracts were washed with  ̃0.1 N HCl and with 5% aqueous sodium hydrogencarbonate solution, dried with sodium sulfate, filtered and concentrated. The residue was purified by column chromatography to provide tert-butyl 4-(bromomethyl)-4-fluoropiperidine-1-carboxylate (60.1 g, 203 mmol, 80% yield).
Step 2: tert-butyl 4-(acetoxymethyl)-4-fluoropiperidine-1-carboxylate
To a mixture of tert-butyl 4-(bromomethyl)-4-fluoropiperidine-1-carboxylate (50 g, 169 mmol) and potassium iodide (7.01 g, 42.2 mmol) in dimethyl formamide (1.5 L) was added potassium acetate (249 g, 2532 mmol) at room temperature. The mixture was stirred at 120-140° C. for 12 h, then cooled, diluted with water, and extracted with ethyl acetate. The combined organic phases were washed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by chromatography on a silica gel column eluted with hexanes:ethyl acetate to give tert-butyl 4-(acetoxymethyl)-4-fluoropiperidine-1-carboxylate (42 g, 153 mmol, 90% yield).
Step 3: (4-fluoropiperidin-4-yl)methyl acetate hydrochloride
To a mixture of tert-butyl 4-(acetoxymethyl)-4-fluoropiperidine-1-carboxylate (50 g, 182 mmol) in ethyl acetate (400 mL) was added a solution of HCl (1 L) at 0° C. The mixture was allowed to warm to 15° C. and stirred at 15° C. overnight. The reaction mixture was concentrated under vacuum, and the residue washed with dichloromethane. Then the precipitate was collected by filtration to obtain (4-fluoropiperidin-4-yl)methyl acetate hydrochloride (33 g, 156 mmol, 86% yield).
Step 4: (1-acetyl-4-fluoropiperidin-4-yl)methyl acetate
To a solution of (4-fluoropiperidin-4-yl)methyl acetate hydrochloride (30 g, 142 mmol) and triethylamine (59.3 mL, 425 mmol) in dichloromethane (300 mL) was added acetyl chloride (16.69 g, 213 mmol) at 0° C. The mixture was stirred overnight at 20° C., then diluted with dichloromethane and washed with water. The dichloromethane layer was concentrated to give crude (1-acetyl-4-fluoropiperidin-4-yl)methyl acetate (21 g, 97 mmol, 68.2% yield).
Step 5: 1-[4-fluoro-4-(hydroxymethyl)-1-piperidyl]ethanone
(1-Acetyl-4-fluoropiperidin-4-yl)methyl acetate (30.8 g, 142 mmol) was dissolved in 3:1 THF:water (400 mL) at 0° C., and then lithium hydroxide (6.80 g, 284 mmol) was added in one portion. The reaction mixture was stirred for 1 hour at 0° C. The mixture was poured into ethyl acetate and water, shaken, and the layers separated. The aqueous layer was extracted with ethyl acetate. The ethyl acetate extracts were combined, dried over Na2SO4, and concentrated under reduced pressure. The residue was titrated with CH2Cl2 and cyclohexane to afford 1-[4-fluoro-4-(hydroxymethyl)-1-piperidyl]ethanone (19 g, 108 mmol, 76% yield). Alternatively, 1-[4-fluoro-4-(hydroxymethyl)-1-piperidyl]ethanone is available by treatment of commercially available (4-fluoropiperidin-4-yl)methanol (CAS: 949100-11-2) with acetic anhydride.
Synthesis of ALC04: 2-[isopropyl(oxetan-3-yl)amino]ethanol




2-[Isopropyl(oxetan-3-yl)amino]ethanol is available by the reaction of (isopropylamino)ethanol (CAS: 109-56-8) with 1 equivalent of 3-oxetanone (CAS: 6704-31-0) in a solvent such as isopropanol or THF with a reducing agent such as sodium borohydride or sodium triacetoxyborohydride, followed by distillation.
Synthesis of ALC05: 2-(oxetan-3-yloxy)ethanol




Step 1: 3-(2-benzyloxyethoxy)oxetane
1.0 M Lithium bis(trimethylsilyl)amide in THF (31.1 mL, 31.1 mmol, 1.2 equiv) was added dropwise at RT to a solution of oxetan-3-ol (1.92 g, 25.9 mmol) and ((2-bromoethoxy)methyl)benzene (6.13 g, 28.5 mmol, 1.1 equiv) in dioxane (15 mL). The mixture was stirred at ambient temperature for 2 hours. DMF (20 mL) was added along with sodium iodide, and the reaction mixture was stirred at ambient temperature overnight, then stirred at 70° C. for 20 hours. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and aqueous citric acid. The organic layer was washed twice with brine, then dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (dichloromethane and ethyl acetate) to give 3-(2-(benzyloxy)ethoxy)oxetane.
Step 2: 2-(oxetan-3-yloxy)ethanol
To a solution of 3-(2-(benzyloxy)ethoxy)oxetane (1.40 g, 6.72 mmol) in THF (28 mL) was added 20% palladium hydroxide on carbon (0.178 g, 0.645 mmol) in a 50 mL pressure bottle, and the mixture was stirred for 4 h under a hydrogen atmosphere. The reaction mixture was filtered free of catalyst and solids, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a mixture of ethyl acetate and dichloromethane to give the titled compound.
Synthesis of Intermediate BF01: potassium trifluorido{[4-(methoxymethyl)piperidin-1-yl]methyl}borate




4-(Methoxymethyl)piperidine hydrochloride ([916317-00-5], 1.0 g, 6.03 mmol), potassium bromomethyl trifluoroborate (1.21 g, 6.03 mmol), KHCO3 (1.2 g, 12.1 mmol) and KI (100 mg, 0.6 mmol) were stirred under N2 in dry THF (8 mL) at 80° C. for 4 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was suspended in dry acetone and filtered. The filtrate was treated with diethyl ether, and the resulting precipitate was collected by filtration and dried to afford the titled compound, which was used as in the next step.







TABLE IX







List of amines













Int.
Structure
Name
SM
method
MW
Mes





AMI01




4- (methoxymethyl) piperidin-4- ol hydrochloride
14780 4-30-6
Specific example
181



 


AMI02




4-[(1,1-dioxo- 1,4-thiazinan- 4- yl)methyl] piperidin-4-ol hydrochloride
14780 4-30-6
Specific example
284



 


AMI03




(2S)-2-fluoro- N,N-dimethyl- 2-(4- piperidyl) ethanamine hydrochloride
14237 4-19-4
Specific example
210



 


AMI04




4- (ethoxymethyl)- 4-fluoro- piperidine
14285 1-03-4
Specific example
161



 


AMI05




4-fluoro-4-(2- methoxyethoxy- methyl) piperidine
61473 0-97-1
Specific example
191



 


AMI06 955082- 95-8 or 955028- 84-9 (HCl salt)




(3R,4R)-3- fluoropiperidin- 4-ol


119



 


AMI07




4-fluoro-4- (methoxymethyl) piperidine
61473 0-97-1
Specific example
147



 


AMI08




3-fluoro-3-(2- methoxyethoxy- methyl) piperidine
12097 81-11- 2
Specific example
191



 


AMI09




2-(4-hydroxy- 4- piperidyl) acetonitrile hydrochloride
79099- 07-3
Specific example
140



 


AMI10




4-methoxy- 1,4′- bipiperidine
19099- 93-5 and 4045- 24-3
Specific example
198



 


AMI11




1-piperidin- 1-ium-4- ylpiperidine- 4- carbonitrile chloride
79099- 07-3 and 4395- 98-6
Specific example
249
















TABLE X







List of alcohols













Int.
Structure
Name
SM
method
MW
Mes





ALC01




(2S)-2-fluoro- 2- tetrahydropyran- 4-yl-ethanol

Analogous to ALC02
148



 


ALC02




(2R)-2-fluoro- 2- tetrahydropyran- 4-yl-ethanol
65626- 23-5
Specific example
148



 


ALC03




1-[4-fluoro-4- (hydroxymethyl)- 1- piperidyl] ethanone
15963 5-49-1
Specific example
175



 


ALC04




2- [isopropyl (oxetan-3- yl)amino]ethanol

Specific example
159



 


ALC05




2-(oxetan-3- yloxy)ethanol

Specific example
118



 


ALC06




(1- cyclobutyl- 4- piperidyl) methanol
6457- 49-4 and 1191- 95-3
I18
169
170


 


ALC07




(1- cyclohexyl- 4- piperidyl) methanol
6457- 49-4 and 108- 94-1
I18
197
198


 


ALC08




(1- tetrahydropyran- 4-yl-4- piperidyl) methanol
6457- 49-4 and 29943- 42-8
I18
199
200


 


ALC09




(1- cyclopropyl- 4- piperidyl) methanol
6457- 49-4 and 27374- 25-0
I26
155
156
















TABLE XI







List of BF3 salts













Int.
Structure
Name
SM
method
MW
Mes





BF01




potassium trifluorido{[4- (methoxymethyl) piperidin-1- yl]methyl} borate
916317- 00-5 and 888711- 44-2
Specific example
249
NA
















TABLE XII







List of esters













Int.
Structure
Name
SM
method
MW
Mes





E001




ethyl 1-(3- bromophenyl)-3- isopropyl-4-(4- morpholinophenyl) pyrazolo[3,4-b] pyridine- 6-carboxylate
A242
I9, Specific example
548- 550
549- 551


 


E002




ethyl 1-[3-(azetidin-1- yl)phenyl]-3- isopropyl-4-(4- morpholinophenyl) pyrazolo[3,4-b] pyridine- 6-carboxylate
E001, 935670- 07-8
I8, Specific example
525
526


 


E003




ethyl 1-cyclohexyl-3- isopropyl-4-(2- morpholinopyrimidin- 5-yl)pyrazolo[3,4- b]pyridine-6- carboxylate
ALP22, AMP23
I1
478
479


 


E004




ethyl 3-methyl-1- phenyl-4-(1- piperidyl)pyrazolo [3,4-b]pyridine-6- carboxylate
HP13, 98-77-1
I3
364
365


 


E005




ethyl 3-isopropyl-4- (4- morpholinophenyl)-1- (3-pyrrolidin-1- ylphenyl)pyrazolo[3,4- b]pyridine-6- carboxylate
E001
I8
539
540


 


E006




ethyl 4-[4- (dimethylamino) phenyl]-3-methyl-1- phenyl-pyrazolo[3,4- b]pyridine-6- carboxylate
ALP25, 1131- 18-6
I1
400
401


 


E007




ethyl 3-isopropyl-4- (6-morpholino-3- pyridyl)-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
ALP26, AMP04
I1
471
472


 


E008




ethyl 3-isopropyl-1- [3-(3- methoxyazetidin-1- yl)phenyl]-4-(4- morpholinophenyl) pyrazolo[3,4-b] pyridine- 6-carboxylate
E001, 110925- 17-2
I8, Specific example
555
556


 


E009




ethyl 3-methyl-4-(6- morpholino-3- pyridyl)-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
ALP26, 1131- 18-6
I1
443
444


 


E010




ethyl 4-(4- bromophenyl)-3- methyl-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
A246
I9
435- 437
436- 438


 


E011




ethyl 4-[4-[3- (dimethylamino) azetidin-1-yl]phenyl]- 3-methyl-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
E010, 138022- 85-2
I10, Specific example
455
456


 


E012




ethyl 1-[3-(3,3- dimethylazetidin-1- yl)phenyl]-3- isopropyl-4-(4- morpholinophenyl) pyrazolo[3,4-b] pyridine- 6-carboxylate
E001, 19816- 92-3
I8
553
554


 


E013




ethyl 1-[3-(3- fluoropyrrolidin-1- yl)phenyl]-3- isopropyl-4-(4- morpholinophenyl) pyazolo[3,4-b] pyridine- 6-carboxylate
E001, 116574- 74-4
I8
553
558


 


E014




ethyl 1-cyclohexyl-3- isopropyl-4-[6- [methyl (tetrahydropyran- 4-yl)amino]-3- pyridyl]pyrazolo[3,4- b]pyridine-6- carboxylate
ALP10, AMP23
I1
505
506


 


E015




ethyl 1-[3- (dimethylamino) phenyl]-3-isopropyl-4- (6-morpholino-3- pyridyl)pyrazolo[3,4- b]pyridine-6- carboxylate
ALP26, AMP06
I1
514
515


 


E016




ethyl 1-[3- (dimethylamino) phenyl]- 3-isopropyl-4-(2- morpholinopyrimidin- 5-yl)pyrazolo[3,4- b]pyridine-6- carboxylate
ALP22, AMP06
I1
515
516


 


E017




ethyl 3-cyclobutyl-4- [6-[2- methoxyethyl(methyl) amino]-3-pyridyl]-1- phenyl-pyrazolo[3,4- b]pyridine-6- carboxylate
ALP08, AMP29
I1
485
486


 


E018




ethyl 4-[6-(4-cyano-1- piperidyl)-3-pyridyl]- 3-cyclobutyl-1- phenyl-pyrazolo[3,4- b]pyridine-6- carboxylate
ALP09, AMP29
I1
506
507


 


E019




ethyl 3-cyclobutyl-4- [6-[methyl (tetrahydropyran- 4-yl)amino]-3- pyridyl]-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
ALP10, AMP29
I1
511
512


 


E020




ethyl 3-cyclobutyl-4- [4-[2-methoxyethyl (methyl) amino]phenyl]-1- phenyl-pyrazolo[3,4- b]pyridine-6- carboxylate
ALP11, AMP29
I1
484
485


 


E021




ethyl 4-(4- acetamidophenyl)-1- cyclohexyl-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
ALP24, AMP23
I1
448
449


 


E022




ethyl 4-[4-(4-cyano-1- piperidyl)phenyl)-1- cyclohexyl-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
ALP12, AMP23
I1
499
500


 


E023




ethyl 4-[4-(4-cyano-1- piperidyl)phenyl]-1- [3- (dimethylamino) phenyl]- 3-isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
ALP12, AMP06
I1
536
537


 


E024




ethyl 1-[3- (dimethylamino) phenyl]-3- isopropyl-4-[4-[2- methoxyethyl (methyl)amino] phenyl]pyrazolo [3,4-b]pyridine-6- carboxylate
ALP11, AMP06
I1
515
516


 


E025




ethyl 4-[6-(4-cyano-1- piperidyl)-3-pyridyl]- 1-[3- (dimethylamino) phenyl]-3-isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
ALP09, AMP06
I1
537
538


 


E026




ethyl 1-[3- (dimethylamino) phenyl]-3-isopropyl- 4-[6-[2- methoxyethyl(methyl) amino]-3- pyridyl]pyrazolo[3,4- b]pyridine-6- carboxylate
ALP08, AMP06
I1
516
517


 


E027




ethyl 4-[6-(4-cyano-1- piperidyl)-3-pyridyl]- 3-isopropyl-1-(3- morpholinophenyl) pyrazolo[3,4-b] pyridine- 6-carboxylate
ALP09, AMP10
I1
579
580


 


E028




ethyl 3-isopropyl-4- [6-[2- methoxyethyl (methyl) amino]-3-pyridyl]-1- (3-morpholinophenyl) pyrazolo[3,4-b] pyridine- 6-carboxylate
ALP08, AMP10
I1
558
559


 


E029




ethyl 3-isopropyl-4- [6-[methyl (tetrahydropyran-4-yl) amino]-3-pyridyl]-1- (3-morpholinophenyl) pyrazolo[3,4-b] pyridine- 6-carboxylate
ALP10, AMP10
I1
584
585


 


E030




ethyl 3-isopropyl-4- [4-[2- methoxyethyl(methyl) amino]phenyl]-1-(3- morpholinophenyl) pyrazolo[3,4-A] pyridine- 6-carboxylate
ALP11, AMP10
I1
557
558


 


E031




ethyl 1-[3- (dimethylamino) phenyl]-3-isopropyl- 4-[6-[methyl (tetrahydropyran- 4-yl)amino]-3- pyridyl]pyrazolo[3,4- b]pyridine-6- carboxylate
ALP10, AMP06
I1
542
543


 


E032




ethyl 1-[3- (dimethylamino) phenyl]-3-isopropyl- 4-[2-[methyl (tetrahydropyran-4- yl)amino]pyrimidin-5- yl]pyrazolo[3,4- b]pyridine-6- carboxylate
ALP13, AMP06
I1
543
544


 


E033




ethyl 1-cyclohexyl-3- cyclopropyl-4-[6- (dimethylamino)-3- pyridyl]pyrazolo[3,4- b]pyridine-6- carboxylate
ALP20, AMP39
I1
433
434


 


E034




ethyl 4-[2-(4-cyano-1- piperidyl)pyrimidin-5- yl]-1-[3- (dimethylamino) phenyl]-3-isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
ALP14, AMP06
I1
538
539


 


E035




ethyl 1-[3- (dimethylamino) phenyl]-3- isopropyl-4-[4-[methyl (tetrahydropyran-4- yl)amino]phenyl] pyrazolo[3,4-b] pyridine-6-carboxylate
ALP15, AMP06
I1
541
542


 


E036




ethyl 3-isopropyl-4- [4-[methyl (tetrahydropyran-4- yl)amino]phenyl]-1- (3-morpholinophenyl) pyrazolo[3,4-b] pyridine-6- carboxylate
ALP15, AMP10
I1
583
584


 


E037




ethyl 4-[2-(4-cyano-1- piperidyl)pyrimidin-5- yl]-3-isopropyl-1-(3- morpholinophenyl) pyrazolo[3,4-b] pyridine- 6-carboxylate
ALP14, AMP10
I1
580
581


 


E038




ethyl 4-[4-[3- (dimethylamino) pyrrolidin-1-yl] phenyl]-3-methyl- 1-phenyl-pyrazolo [3,4-b]pyridine-6- carboxylate
E010, 69478- 75-7
I10
469
470


 


E039




ethyl 3-isopropyl-1- (m-tolyl)-4-(1- piperidyl)pyrazolo [3,4-b]pyridine-6- carboxylate
HP01, 98-77-1
I3
406
407


 


E040




ethyl 4-[4-(4-cyano-1- piperidyl)phenyl]-3- cyclobutyl-1- cyclohexyl- pyrazolo(3,4- b]pyridine-6- carboxylate
ALP12, AMP35
I1
511
512


 


E041




ethyl 4-[6-(4-cyano-1- piperidyl)-3-pyridyl]- 3-cyclobutyl-1- cyclohexyl- pyrazolo[3,4- b]pyridine-6- carboxylate
ALP09, AMP35
I1
512
513


 


E042




ethyl 4-(4- acetamidophenyl)-1- (3,5-difluorophenyl)- 3-(1- methoxycarbonylazetidin- 3-yl)pyrazolo[3,4- b]pyridine-6- carboxylate
E043
I11, Specific example
549
550


 


E043




ethyl 4-(4- acetamidophenyl)-3- (azetidin-3-yl)-1-(3,5- difluorophenyl)pyrazolo [3,4-b]pyridine-6- carboxylate
E044
Specific example
491
492


 


E044




ethyl 4-(4- acetamidophenyl)-3- (1-tert- butoxycarbonylazetidin- 3-yl)-l-(3,5- difluorophenyl)pyrazolo [3,4-b]pyridine-6- carboxylate
ALP24, AMP40
I1
591
592


 


E045




ethyl 3-isopropyl-4- [4-[2- methoxyethyl(methyl) amino]phenyl]-1-(3- pyrrolidin-1- ylphenyl)pyrazolo[3,4- b]pyridine-6- carboxylate
ALP11, AMP11
I1
541
542


 


E046




ethyl 3-isopropyl-4- [4- [methyl(tetrahydropyran- 4-yl)amino]phenyl]-1- (3-pyrrolidin-1- ylphenyl)pyrazolo[3,4- b]pyridine-6- carboxylate
ALP15, AMP11
I1
567
568


 


E047




ethyl 3-cyclobutyl-4- [4-[methyl (tetrahydropyran-4- yl)amino]phenyl]-1- (3-pyrrolidin-1- ylphenyl)pyrazolo[3,4- b]pyridine-6- carboxylate
ALP15, AMP31
I1
580
581


 


E048




ethyl 3-isopropyl-4- (4-methoxy-1- piperidyl)-1-(m- tolyl)pyrazolo[3,4- b]pyridine-6- carboxylate
HP01, 4045- 24-3
I3
436
437


 


E049




ethyl 4-[2-(4-cyano-1- piperidyl)pyrimidin-5- yl]-1-cyclohexyl-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
ALP14, AMP23
I1
501
502


 


E050




ethyl 1-cyclohexyl-3- isopropyl-4-[2-[2- methoxyethyl(methyl) amino]pyrimidin-5- yl]pyrazolo[3,4- b]pyridine-6- carboxylate
ALP16, AMP23
I1
480
481


 


E051




ethyl 1-cyclohexyl-3- isopropyl-4-[2- [methyl (tetrahydropyran-4- yl)amino]pyrimidin-5- yl]pyrazolo[3,4- b]pyridine-6- carboxylate
ALP13, AMP23
I1
506
507


 


E052




ethyl 4-[6-(4-cyano-1- piperidyl)-3-pyridyl]- 3-isopropyl-1-[3- (trifluoromethyl)phenyl] pyrazolo[3,4- b]pyridine-6- carboxylate
ALP09, AMP08
I1
562
563


 


E053




ethyl 1-[6- (dimethylamino)-2- pyridyl]-3-isopropyl- 4-(4- morpliolinophenyl) pyrazolo[3,4-b]pyridine- 6-carboxylate
ALP18, AMP18
I1
514
515


 


E054




ethyl 3-isopropyl-4-(4- morpholinophenyl)-1- [3-(trifluoromethoxy) phenyl]pyrazolo[3,4- b]pyridine-6- carboxylate
E055, 179113- 90-7
I4
554
555


 


E055




ethyl 3-isopropyl-4- (4- morpholinophenyl)- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E056
I15, Specific example
394
395


 


E056




ethyl 1-[(2,4- dimethoxyphenyl) methyl]-3-isopropyl-4-(4- morpholinophenyl) pyrazolo[3,4-b]pyridine- 6-carboxylate
ALP18, AMP28
I1
544
545


 


E057




ethyl 1-(3,4- difluorophenyl)-3- isopropyl-4-(4- morpholinophenyl) pyrazolo[3,4-b]pyridine- 6-carboxylate
E055
I4
506
507


 


E058




ethyl 3-isopropyl-4- (4- morpholinophenyl)-1- (6-morpholino-2- pyridyl)pyrazolo[3,4- b]pyridine-6- carboxylate
ALP18, AMP19
I1
556
557


 


E059




ethyl 4-(2,6-difluoro- 4-methoxy-phenyl)-1- (3-fluoro-5-methoxy- phenyl)-3-methyl- pyrazolo[3,4- b]pyridine-6- carboxylate
ALP17, AMP03
I1
471
472


 


E060




ethyl 4-[4-(4-cyano-1- piperidyl)phenyl)-1- (3,5-difluorophenyl)- 3-isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
ALP12, AMP09
I1
529
530


 


E061




ethyl 4-[4-(4-cyano-1- piperidyl)phenyl]-1- (3-fluorophenyl)-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
ALP12, AMP12
I1
511
512


 


E062




ethyl 3-isopropyl-4- [4-[2- methoxyethyl(methyl) amino]phenyl]-1-[3- (trifluoromethyl)phenyl] pyrazolo[3,4- b]pyridine-6- carboxylate
ALP11, AMP08
I1
540
541


 


E063




ethyl 3-isopropyl-4- [6- [methyl(tetrahydrapyran- 4-yl)amino]-3- pyridyl]-1-[3- (trifluoromethyl)phenyl] pyrazolo[3,4- b]pyridine-6- carboxylate
ALP10, AMP08
I1
567
568


 


E064




ethyl 1-(4- fluorophenyl)-3- isopropyl-4-[2- [methyl(tetrahydropyran- 4- yl)amino]pyrimidin-5- yl]pyrazolo[3,4- b]pyridine-6- carboxylate
ALP13, AMP13
I1
518
519


 


E065




ethyl 4-[4-(4-cyano-1- piperidyl)phenyl]-3- isopropyl-1-[3- (trifluoromethyl) phenyl]pyrazolo[3,4- b]pyridine-6- carboxylate
ALP12, AMP08
I1
561
562


 


E066




ethyl 3-isopropyl-4- (4- morpholinophenyl)-1- (2-morpholino-4- pyridyl)pyrazolo[3,4- b]pyridine-6- carboxylate
ALP18, AMP21
I1
556
557


 


E067




ethyl 3-(1- methylcyclobutyl)-4 (4- morpholinophenyl)-1- phenyl-pyrazolo[3,4- b]pyridine-6- carboxylate
ALP18, AMP41
I1
496
497


 


E068




ethyl 4-[2-(4-cyano-1- piperidyl)pyrimidin-5 yl]-1-(2,4- difluorophenyl)-3- isopropyl- pyrazolo(3,4- b]pyridine-6- carboxylate
ALP14, AMP14
I1
531
532


 


E069




ethyl 4-[6-(4-cyano-1- piperidyl)-3-pyridyl] 1-(2,4- difluorophenyl)-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
ALP09, AMP14
I1
530
531


 


E070




ethyl 4-[4-(4-cyano-1- piperidyl)phenyl)-1- (2,4-difluorophenyl)- 3-isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
ALP12, AMP14
I1
529
530


 


E071




methyl 3-cyclobutyl- 4-(4-methoxy-1- piperidyl)-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
420
421


 


E072




ethyl 1-[3- (dimethylamino)phenyl]- 3-isopropyl-4-[4- (methoxymethyl)-1- piperidyl]pyrazolo[3,4- b]pyridine-6- carboxylate
HP03
I3
479
480


 


E073




ethyl 4-[6-(4-cyano-1- piperidyl)-3-pyridyl]- 3-isopropyl-1- tetrahydropyran-3-yl- pyrazolo[3,4- b]pyridine-6- carboxylate
ALP09, AMP25
I1
502
503


 


E074




methyl 4-(4- bromophenyl)-1-[3- (dimethylamino) phenyl]-3-isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
608128- 34-3, AMP06
I1
492- 494
493- 495


 


E075




ethyl 4-(2,2-difluoro- 5-azaspiro[2.4]heptan- 5-yl)-3-isopropyl-1- (m-tolyl)pyrazolo[3,4- b]pyridine-6- carboxylate
HP01
I3
454
455


 


E076




ethyl 1-cyclohexyl-3- isopropyl-4-(4- methoxy-1- piperidyl)pyrazolo[3,4- b]pyridine-6- carboxylate
HP04
I3
428
429


 


E077




methyl 3-cyclobutyl- 4-(4-isopropoxy-1- piperidyl)-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
448
449


 


E078




methyl 3-cyclobutyl- 1-phenyl-4-(4- propoxy-1- piperidyl)pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
448
449


 


E079




methyl 3-cyclobutyl- 4-[3- (methoxymethyl)-1- piperidyl]-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
434
435


 


E080




methyl 3-cyclobutyl- 4-[4-(2-oxo-2- pyrrolidin-1-yl- ethoxy)-1-piperidyl]- 1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
517
518


 


E081




ethyl 1-[3- (dimethylamino)phenyl]- 3-isopropyl-4-(4- methoxy-1- piperidyl)pyrazolo[3,4- b]pyridine-6- carboxylate
HP03
I3
465
466


 


E082




ethyl 3-isopropyl-4- [4-(methoxymethyl)- 1-piperidyl]-1-(m- tolyl)pyrazolo[3,4- b]pyridine-6- carboxylate
HP01
I3
450
451


 


E083




ethyl 1-[3- (dimethylamino)phenyl]- 3-isopropyl-4-(1- piperidyl)pyrazolo[3,4- b]pyridine-6- carboxylate
HP03
I3
435
436


 


E084




ethyl 4-[6-(4-cyano-1- piperidyl)-3-pyridyl]- 3-isopropyl-1-(2- pyrrolidin-1-yl-4- pyridyl)pyrazolo[3,4- b]pyridine-6- carboxylate    
ALP09, AMP22
I1
564
565


 


E085




methyl 3-cyclobutyl- 4-(1-oxa-7- azaspiro[3.5]nonan-7- yl)-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
432
433


 


E086




ethyl 4-(4-cyano-1- piperidyl)-1-[3- (dimethylamino) phenyl]-3-isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP03
I3
460
461


 


E087




ethyl 3-isopropyl-4- [4-(2-methoxyethyl)- 1-piperidyl]-1-(m- tolyl)pyrazolo[3,4- b]pyridine-6- carboxylate
HP01
I3
464
465


 


E088




ethyl 3-isopropyl-4- (3-methoxy-1- piperidyl)-1-(m- tolyl)pyrazolo[3,4- b]pyridine-6- carboxylate
HP01
I3
436
437


 


E089




ethyl 3-isopropyl-4- (4-methylsulfonyl-1- piperidyl)-1-(m- tolyl)pyrazolo[3,4- b]pyridine-6- carboxylate
HP01
I3
484
485


 


E090




isopropyl 3- isopropoxy-4-(4- morpholinophenyl)-1- phenyl-pyrazolo[3,4- b]pyridine-6- carboxylate
A256
I17, Specific example
500
501


 


E091




methyl 1-(4- fluorophenyl)-3- isopropyl-4-(4- methoxy-1- piperidyl)pyrazolo[3,4- b]pyridine-6- carboxylate
HP05
I3
426
427


 


E092




methyl 1-(4- fluorophenyl)-3- isopropyl-4-[4- (methoxymethyl)-1- piperidyl]pyrazolo[3,4- b]pyridine-6- carboxylate
HP05
I3, Specific example
440
441


 


E093




ethyl 4-[4-(4-cyano-1- piperidyl)phenyl]-3- isopropyl-1-(2- pyrrolidin-1-yl-4- pyridyl)pyrazolo[3,4- b]pyridine-6- carboxylate
ALP12, AMP22
I1
563
564


 


E094




ethyl 3-isopropyl-4- [2- methoxyethyl(methyl) amino]-1-(m- tolyl)pyrazolo[3,4- b]pyridine-6- carboxylate
HP01
I1
410
411


 


E095




ethyl 3-isopropyl-1- (m-tolyl)-4-(8-oxa-2- azaspiro[4.5]decan-2- yl)pyrazolo[3,4- b]pyridine-6- carboxylate
HP01
I3
462
463


 


E096




methyl 4-(4-butoxy-1- piperidyl)-1-(4- fluorophenyl)-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP05
I3
468
467


 


E097




methyl 1-(4- fluorophenyl)-3- isopropyl-4-(4- methoxy-4-methyl-1- piperidyl)pyrazolo[3,4- b]pyridine-6- carboxylate
HP05
I3
440
441


 


E098




methyl 1-(4- fluorophenyl)-4-(4- isobutoxy-1- piperidyl)-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP05
I3
468
469


 


E099




methyl 1-(4- fluorophenyl)-3- isopropyl-4-(1-oxa-7- azaspiro[3.5]nonan-7- yl)pyrazolo[3,4- b]pyridine-6- carboxylate
HP05
I3
438
439


 


E100




methyl 4-[3- (difluoromethyl)-1- piperidyl]-1-(4- fluorophenyl)-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP05
I3
446
447


 


E101




methyl 1-(4- fluorophenyl)-3- isopropyl-4-(6-oxa-2- azaspiro[3.5]nonan-2- yl)pyrazolo[3,4- b]pyridine-6- carboxylate
HP05
I3
438
439


 


E102




methyl 1-(4- fluorophenyl)-3- isopropyl-4-(1-oxa-8- azaspiro[4.5]decan-8- yl)pyrazolo[3,4- b]pyridine-6- carboxylate
HP05
I3
452
453


 


E103




methyl 3-cyclobutyl- 1-phenyl-4-(1- piperidyl)pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
390
391


 


E104




methyl 3-cyclobutyl- 4-[4-(2- methoxyethyl)-1- piperidyl]-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
448
449


 


E105




methyl 4-(2- azaspiro[3.4]octan-2- yl)-3-cyclobutyl-1- phenyl-pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
416
417


 


E106




methyl 3-cyclobutyl- 4-[4- (methoxymethyl)-1- piperidyl]-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
434
435


 


E107




methyl 4-(3- azabicyclo[3.1.0]hexan- 3-yl)-3-cyclobutyl- 1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
388
389


 


E108




ethyl 1-(2-bromo-4- pyridyl)-3-isopropyl- 4-(4-methoxy-1- piperidyl)pyrazolo[3,4- b]pyridine-6- carboxylate
E109
I4
501- 503
502- 504


 


E109




ethyl 3-isopropyl-4- (4-methoxy-1- piperidyl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
HP08
I3
346
347


 


E110




ethyl 3-isopropyl-4- (4-methoxy-1- piperidyl)-1-(2- pyrrolidin-1-yl-4- pyridyl)pyrazolo[3,4- b]pyridine-6- carboxylate
E111
I12, Specific example
492
493


 


E111




ethyl 1-(2-fluoro-4- pyridyl)-3-isopropyl- 4-(4-methoxy-1- piperidyl)pyrazolo[3,4- b]pyridine-6- carboxylate
E109
I4, Specific example
441
442


 


E112




ethyl 4-[6-(4-cyano-1- piperidyl)-3-pyridyl]- 3-cyclobutyl-1-(2- pyrrolidin-1-yl-4- pyridyl)pyrazolo[3,4- b]pyridine-6- carboxylate
ALP09, AMP34
I1
576
577


 


E113




methyl 3-cyclobutyl- 4-(4-methylsulfonyl- 1-piperidyl)-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
468
469


 


E114




methyl 4-(4-cyano-1- piperidyl)-3- cyclobutyl-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
415
416


 


E115




methyl 4-(2- azaspiro[3.5]nonan-2- yl)-3-cyclobutyl-1- phenyl-pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
430
431


 


E116




methyl 3-cyclobutyl- 4-[3-(methoxymethyl) azetidin-1-yl]-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
406
407


 


E117




ethyl 4-[6-(4-cyano-1- piperidyl)-3-pyridyl]- 3-(3- methoxycyclobutyl)- 1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
ALP09, AMP42
I1
536
537


 


E118




ethyl 4-[6-(4-cyano-1- piperidyl)-3-pyridyl]- 3-(3,3- difluorocyclobutyl)-1- phenyl-pyrazolo[3,4- b]pyridine-6- carboxylate
ALP09, AMP43
I1
542
543


 


E119




ethyl 4-[6-(4-cyano-1- piperidyl)-3-pyridyl]- 3-(3,3- dimethylcyclobutyl)- 1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
ALP09, AMP44
I1
534
535


 


E120




ethyl 4-[6-(4-cyano-1- piperidyl)-3-pyridyl]- 3-(3- fluorocyclobutyl)-1- phenyl-pyrazolo[3,4- b]pyridine-6- carboxylate
ALP09, AMP45
I1
524
525


 


E121




ethyl 4-[6-(4-cyano-1- piperidyl)-3-pyridyl]- 3-cyclobutyl-1-(2- morpholino-4- pyridyl)pyrazolo[3,4- b]pyridine-6- carboxylate
ALP09, AMP33
I1
592
593


 


E122




methyl 3-cyclobutyl- 4-(2,2-difluoro-5- azaspiro[2.4]heptan-5- yl)-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
438
439


 


E123




methyl 3-cyclobutyl- 4-(5-oxa-2- azaspiro[3.5]nonan-2- yl)-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
432
433


 


E124




methyl 3-cyclobutyl- 4-(7-oxa-2- azaspiro[3.5]nonan-2- yl)-1-phenyl- pyrazolo(3,4- b]pyridine-6- carboxylate
HP02
I3
432
433


 


E125




methyl 4-(5- azaspiro[2.5]octan-5- yl)-3-cyclobutyl-1- phenyl-pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
416
417


 


E126




methyl 3-cyclobutyl- 4-[2- methoxyethyl(methyl) amino]-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
394
395


 


E127




methyl 4-[4- (benzyloxymethyl)-1- piperidyl]-3- cyclobutyl-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
510
511


 


E128




methyl 4-(2- azaspiro[3.3]heptan-2- yl)-3-cyclobutyl-1- phenyl-pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
402
403


 


E129




methyl 3-cyclobutyl- 4-(1- methoxycarbonyl- 3,3a,4,6,7,7a- hexahydro-2H- pyrrolo[3,2-c]pyridin- 5-yl)-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
E130
I11, Specific example
489
490


 


E130




methyl 4- (1,2,3,3a,4,6,7,7a- octahydropyrrolo[3,2- c]pyridin-5-yl)-3- cyclobutyl-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
E131
Specific example
431
432


 


E131




methyl 4-(1-tert- butoxycarbonyl- 3,3a,4,6,7,7a- hexahydro-2H- pyrrolo[3,2-c]pyridin- 5-yl)-3-cyclobutyl-1- phenyl-pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
531
532


 


E132




methyl 4-(1-acetyl- 3,3a,4,6,7,7a- hexahydro-2H- pyrrolo[3,2-c]pyridin- 5-yl)-3-cyclobutyl-1- phenyl-pyrazolo[3,4- b]pyridine-6- carboxylate
E130
I11, Specific example
473
474


 


E133




ethyl 1-(6-bromo-2- pyridyl)-3-isopropyl- 4-(4-methoxy-1- piperidyl)pyrazolo[3,4- b]pyridine-6- carboxylate
E109
I5, Specific example
501- 503
502- 504


 


E134




methyl 1-cyclohexyl- 4-[4-(hydroxymethyl)- 1-piperidyl]-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP12
I3
414
415


 


E135




methyl 3-cyclobutyl- 4-[4-[(1S)-2- (dimethylamino)-1- fluoro-ethyl]-1- piperidyl]-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02, AMI03
I3
479
480


 


E136




methyl 1-(4- fluorophenyl)-4-[4-(1- hydroxy-1-methyl- ethyl)-1-piperidyl]-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP05
I3
454
455


 


E137




ethyl 1-(3- fluorophenyl)-5- isopropyl-4-[6- [methyl(tetrahydropyan- 4-yl)amino]-3- pyridyl]pyrazolo[3,4- b]pyridine-6- carboxylate
ALP10, AMP12
I1
517
518


 


E138




ethyl 4-[6-(4-cyano-1- piperidyl)-3-pyridyl]- 3-isopropyl-1-(2- morpholino-4- pyridyl)pyrazolo[3,4- b]pyridine-6- carboxylate
ALP09, AMP21
I1
580
581


 


E139




methyl 3-cyclobutyl- 4-[4-(cyclopentoxy)- 1-piperidyl]-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
474
475


 


E140




methyl 3-cyclobutyl- 4-[4-(cyclohexoxy)-1- piperidyl]-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
488
489


 


E141




methyl 3-cyclobutyl- 4-[4- (cyclopropylmethoxy)- 1-piperidyl]-1- phenyl-pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
460
461


 


E142




ethyl 4-(4-cyano-1- piperidyl)-1-(4- fluorophenyl)-3- isopropyl- pyrazolo[3,4- bb]pyridine-6- carboxylate
HP09
I3
435
436


 


E143




methyl 3-cyclobutyl- 4-[4-(1- hydroxyethyl)-1- piperidyl]-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
434
435


 


E144




methyl 3-cyclobutyl- 1-phenyl-4-[4-(2,2,2- trifluoro-1-hydroxy-1- methyl-ethyl)-1- piperidyl]pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
502
503


 


E145




ethyl 4-[6-[bis(2- methoxyethyl)amino]- 3-pyridyl]-3- cyclobutyl-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
ALP23, AMP29
I1
529
530


 


E146




methyl 3-cyclobutyl- 4-[4-hydroxy-4- (methoxymethyl)-1- piperidyl]-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02, AMI01
I3
450
451


 


E147




ethyl 1-(2-fluoro-4- pyridyl)-3-isopropyl- 4-[4- (methoxymethyl)-1- piperidyl]pyrazolo[3,4- b]pyridine-6- carboxylate
E148
I4
455
456


 


E148




ethyl 3-isopropyl-4- [4-(methoxymethyl)- 1-piperidyl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
HP08
I3
360
361


 


E149




ethyl 4-[6-[bis(2- methoxyethyl)amino]- 3-pyridyl]-3- isopropyl-1-(2- morpholino-4- pyridyl)pyrazolo[3,4- b]pyridine-6- carboxylate
ALP23, AMP21
I1
603
604


 


E150




methyl 3-cyclobutyl- 4-[4-[(1,1-dioxo-1,4- thiazinan-4- yl)methyl]-4-hydroxy- 1-piperidyl]-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02, AMI02
I3
553
554


 


E151




ethyl 4-[6-(4-cyano-1- piperidyl)-3-pyridyl]- 3-(3- methylcyclobutyl)-1- phenyl-pyrazolo[3,4- b]pyridine-6- carboxylate
ALP09, AMP46
I1
520
521


 


E152




ethyl 3-[(1-tert- butoxycarbonyl-4- piperidyl)oxy]-4-[6- (4-cyano-1-piperidyl)- 3-pyridyl]-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
E153
I13, Specific example
651



 


E153




ethyl 4-[6-(4-cyano-1- piperidyl)-3-pyridyl]- 3-oxo-1-phenyl-2H- pyrazolo[3,4- b]pyridine-6- carboxylate
ALP09, 70373- 98-7
I1
468
469


 


E154




ethyl 1- (cyclobutylmethyl)-3- isopropyl-4-[4- (methoxymethyl)-1- piperidyl]pyrazolo[3,4- b]pyridine-6- carboxylate
E148
I6, Specific example
428
429


 


E155




ethyl 1-isobutyl-3- isopropyl-4-[4- (methoxymethyl)-1- piperidyl]pyrazolo[3,4- b]pyridine-6- carboxylate
E148
I6
416
417


 


E156




methyl 1-(4- fluorophenyl)-3- isopropyl-4-[4-(2,2,2- trifluoroethyl)piperazin- 1-yl]pyrazolo[3,4- b]pyridine-6- carboxylate
HP05
I3
479
480


 


E157




ethyl 3-isopropyl-4- [4-(methoxymethyl)- 1-piperidyl]-1-(1- methyl-6-oxo- pyridazin-3- yl)pyrazolo[3,4- b]pyridine-6- carboxylate
E148
I7
468
469


 


E158




methyl 3-cyclobutyl- 4-(4- isopropylpiperazin-1- yl)-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
433
434


 


E159




ethyl 4-[6-(4-cyano-1- piperidyl)-3-pyridyl]- 1-phenyl-3- tetrahydrofuran-3- yloxy-pyrazolo[3,4- b]pyridine-6- carboxylate
E153
I13
538
539


 


E160




ethyl 3-isopropyl-4- [4-(methoxymethyl)- 1-piperidyl]-1-(2- morpholinopyrimidin- 4-yl)pyrazolo[3,4- b]pyridine-6- carboxylate
E161
I12
523
524


 


E161




ethyl 1-(2- chloropyrimidin-4-yl)- 3-isopropyl-4-[4- (methoxymethyl)-1- piperidyl]pyrazolo[3,4- b]pyridine-6- carboxylate
E148
I5
472- 474
473- 475


 


E162




methyl 4-(4- cyclobutylpiperazin-1- yl)-1-(4- fluorophenyl)-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP05
I3
451
452


 


E163




methyl 3-cyclobutyl- 4-[4-(1-hydroxy-1- methyl-ethyl)-1- piperidyl]-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
448
449


 


E164




ethyl 4-[6-(4-cyano-1- piperidyl)-3-pyridyl]- 3-(oxetan-3-yloxy)-1- phenyl-pyrazolo[3,4- b]pyridine-6- carboxylate
E153
I13
524
525


 


E165




methyl 1-(4- fluorophenyl)-3- isopropyl-4-[2- methoxyethyl(methyl) amino]pyrazolo[3,4- b]pyridine-6- carboxylate
HP05
I3
400
401


 


E166




methyl 1-(4- fluorophenyl)-4-[4-(1- hydroxy-1-methyl- ethyl)-1-piperidyl]-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP05
I3
454
455


 


E167




ethyl 3-cyclobutyl-1- (4-fluorophenyl)-4-[4- (methoxymethyl)-1- piperidyl]pyrazolo[3,4- b]pyridine-6- carboxylate
E168
I4
466
467


 


E168




ethyl 3-cyclobutyl-4- [4-(methoxymethyl)- 1-piperidyl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E169
I15
372
373


 


E169




ethyl 3-cyclobutyl-1- [(2,4- dimethoxyphenyl) methyl]-4-[4- (methoxymethyl)-1- piperidyl]pyrazolo[3,4- b]pyridine-6- carboxylate
HP14
I3
522
523


 


E170




methyl 3-cyclobutyl- 4-[4-(1-hydroxy-1- methyl-ethyl)-1- piperidyl]-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
448
449


 


E171




ethyl 3-cyclobutyl-1- (4-fluorophenyl)-4- (tetrahydropyran-4- ylmethoxy)pyrazolo[3, 4-b]pyridine-6- carboxylate
E172
I16, Specific example
453
454


 


E172




ethyl 3-cyclobutyl-4- (tetrahydropyran-4- ylmethoxy)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E173
I15
359
360


 


E173




ethyl 3-cyclobutyl-1- [(2,4- dimethoxyphenyl) methyl]-4- (tetrahydropyran-4- ylmethoxy)pyrazolo[3, 4-b]pyridine-6- carboxylate
HP15
I14
509
510


 


E174




methyl 4-[4- (dimethylamino)-1- piperidyl]-1-(4- fluorophenyl)-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP05
I3
439
440


 


E175




methyl 1-(4- fluorophenyl)-3- isopropyl-4-[4-(1- methyl-4-piperidyl)-1- piperidyl]pyrazolo[3,4- b]pyridine-6- carboxylate
HP05
I3
493
494


 


E176




methyl 4-[(1-acetyl-4- piperidyl)methoxy]-1- (4-fluorophenyl)-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
E177
I11, Specific example
468
469


 


E177




methyl 1-(4- fluorophenyl)-3- isopropyl-4-(4- piperidylmethoxy) pyrazolo[3,4-b]pyridine- 6-carboxylate
A263
I9
426
427


 


E178




methyl 1-(4- fluorophenyl)-3- isopropyl-4-[(1- methoxycarbonyl-4- piperidyl)methoxy] pyrazolo[3,4-b]pyridine- 6-carboxylate
E177
I11, Specific example
484
485


 


E179




methyl 4-[4- (cyanomethyl)-4- hydroxy-1-piperidyl]- 3-cyclobutyl-1- phenyl-pyrazolo[3,4- b]pyridine-6- carboxylate
HP02, AMI09
I3
445
446


 


E180




methyl 3-cyclobutyl- 1-phenyl-4-[4-(2,2,2- trifluoroethyl)piperazin- 1-yl]pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
473
474


 


E181




ethyl 1-(2-fluoro-4- pyridyl)-3-isopropyl- 4-(tetrahydropyran-4- ylmethoxy)pyrazolo[3, 4-b]pyridine-6- carboxylate
E182
I4
442
443


 


E182




ethyl 3-isopropyl-4- (tetrahydropyran-4- ylmethoxy)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E183
I15
347
348


 


E183




ethyl 1-[(2,4- dimethoxyphenyl) methyl]-3-isopropyl-4- (tetrahydropyran-4- ylmethoxy)pyrazolo[3, 4-b]pyridine-6- carboxylate
HP06
I14, Specific example
497
498


 


E184




methyl 4-(4- ethoxycarbonylpiperazin- 1-yl)-1-(4- fluorophenyl)-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP05
I3
469
470


 


E185




methyl 1-(4- fluorophenyl)-3- isopropyl-4-(3- methyl-2-oxo-1-oxa- 3,8- diazaspiro[4.5]decan- 8-yl)pyrazolo[3,4- b]pyridine-6- carboxylate
HP05
I3
481
482


 


E186




methyl 1-(4- fluorophenyl)-3- isopropyl-4-[3- (trifluoromethyl) piperazin-1- yl]pyrazolo[3,4- b]pyridine-6- carboxylate
HP05
I3
465
466


 


E187




methyl 1-(4- fluorophenyl)-3- isopropyl-4-[4-(2- methoxyethyl)piperazin- 1-yl]pyrazolo[3,4- b]pyridine-6- carboxylate
HP05
I3
455
456


 


E188




methyl 4-(2,4-dioxo- 1,3,8- triazaspiro[4.5]decan- 8-yl)-1-(4- fluorophenyl)-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP05
I3
480
481


 


E189




methyl 4-[4- (ethoxymethyl)-4- fluoro-1-piperidyl]-1- (4-fluorophenyl)-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP05, AMI04
I3
472
473


 


E190




methyl 4-[4-fluoro-4- (2- methoxyethoxymethyl)- 1-piperidyl]-1-(4- fluorophenyl)-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP05, AMI05
I3
502
503


 


E191




methyl 4-[(3R,4R)-3- fluoro-4-hydroxy-1- piperidyl]-1-(4- fluorophenyl)-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP05, AMI06
I3
430
431


 


E192




methyl 4-[4-fluoro-4- (methoxymethyl)-1- piperidyl]-1-(4- fluorophenyl)-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP05, AMI07
I3
458
459


 


E193




methyl 4-[3-fluoro-3- (2- methoxyethoxymethyl)- 1-piperidyl]-1-(4- fluorophenyl)-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP05, AMI08
I3
502
503


 


E194




methyl 1-(4- fluorophenyl)-3- isopropyl-4-[4-(1- piperidyl)-1- piperidyl]pyrazolo[3,4- b]pyridine-6- carboxylate
HP05
I3
479
480


 


E195




ethyl 1-(2,6-dimethyl- 4-pyridyl)-3- isopropyl-4-[4- (methoxymethyl)-1- piperidyl]pyrazolo[3,4- b]pyridine-6- carboxylate
E148
I4
465
466


 


E196




methyl 3-cyclobutyl- 4-(1,1-dioxo-1,4- thiazinan-4-yl)-1- phenyl-pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
440
441


 


E197




methyl 4-(1-tert- butoxycarbonyl-4- piperidyl)-1-(4- fluorophenyl-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
E198
Specific example
496
497


 


E198




methyl 4-(1-tert- butoxycarbonyl-3,6- dihydro-2H-pyridin-4- yl)-1-(4- fluorophenyl)-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP05
I2, Specific example
494
495


 


E199




methyl 4-(4- azidophenyl)-1-[3- (dimethylamino) phenyl]-3-isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
E074
Specific example
455
456


 


E352




methyl 3-cyclobutyl- 1-(4-fluorophenyl)-4- (4-hydroxypiperidin- 1-yl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
HP19
I3
424
425


 


E353




methyl 3-cyclobutyl- 1-(4-fluorophenyl)-4- (4-oxopiperidin-1-yl)- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E352
Specific example
422
423


 


E354




methyl 3-cyclobutyl- 1-(4-fluorophenyl)-4- {4-[2-(methoxymethyl) morpholin-4-yl] piperidin-1- yl}-1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E353
Specific example
537
538


 


E355




methyl 3-cyclobutyl- 1-(4-fluorophenyl)-4- [4-(4- isopropylpiperazin-1- yl)-1- piperidyl]pyrazolo[3,4- b]pyridine-6- carboxylate
HP19, 202991- 78-4
I3
534
535


 


E356




methyl 3-cyclobutyl- 1-(4-fluorophenyl)-4- [4-(4-methoxy-1- piperidyl)-1- piperidyl]pyrazolo[3,4- b]pyridine-6- carboxylate
HP19, AMI10
I3, Specific example
522
523


 


E357




methyl 3-cyclobutyl- 1-phenyl-4-{4- [(pyrrolidin-1- yl)methyl]piperidin-1- yl}-1H-pyrazolo[3,4- b]pyridine-6- carboxylate
HP02, 683772- 11-4
I3, Specific example
473
474


 


E358




methyl 3-cyclobutyl- 4-(4,4-difluoro[1,4′- bipiperidin]-1′-yl)-1- (4-fluorophenyl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E353
I18
527
528


 


E359




methyl 4-[4-(2- cyanomorpholin-4- yl)piperidin-1-yl]-3- cyclobutyl-1-(4- fluorophenyl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E353
I18
518
519


 


E360




methyl 3-cyclobutyl- 1-(4-fluorophenyl)-4- [4-(2-oxa-5- azabicyclo[2.2.1]heptan- 5-yl)piperidin-1-yl]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E353
I18
505
506


 


E361




methyl 3-cyclobutyl- 1-(4-fluorophenyl)-4- {4-[methyl(oxan-4- yl)amino]piperidin-1- yl}-1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E353
I18
521
522


 


E362




methyl 3-cyclobutyl- 1-(4-fluorophenyl)-4- {4-[3-(trifluoromethyl) pyrrolidin-1-yl]piperidin- 1-yl}-1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E353
I18
545
546


 


E363




methyl 4-[4-(3- cyanopyrrolidin-1- yl)piperidin-1-yl]-3- cyclobutyl-1-(4- fluorophenyl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E353
I18
502
503


 


E364




methyl 4-(3- cyano[1,4′- bipiperidin]-1′-yl)-3- cyclobutyl-1-(4- fluorophenyl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E353
I18
516
517


 


E365




methyl 3-cyclobutyl- 4-(3-fluoro[1,4′- bipiperidin]-1′-yl)-1- (4-fluorophenyl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E353
I18
509
510


 


E366




methyl 3-cyclobutyl- 1-(4-fluorophenyl)-4- [4-(3- methoxyazetidin-1- yl)piperidin-1-yl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E353
I18
493
494


 


E367




methyl 3-cyclobutyl- 1-(4-fluorophenyl)-4- [3- (trifluoromethyl)[1,4′- bipiperidin]-1′-yl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E353
I18
559
560


 


E368




methyl 3-cyclobutyl- 1-(4-fluorophenyl)-4- (3-methoxy[1,4′- bipiperidin]-1′-yl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E353
I18
521
522


 


E369




methyl 3-cyclobutyl- 4-[4-(2,2- dimethylmorpholin-4- yl)piperidin-1-yl]-1- (4-fluorophenyl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E353
I18
521
522


 


E370




methyl 3-cyclobutyl- 4-{4-[4- (ethoxycarbonyl) piperazin-1- yl]piperidin-1- yl}-1-(4- fluorophenyl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E353
I18
564
565


 


E371




methyl 3-cyclobutyl- 1-(4-fluorophenyl)-4- [1-(propan-2- yl)octahydro-5H- pyrrolo[3,2-c]pyridin- 5-yl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E514
I33
491
492


 


E372




methyl 3-cyclobutyl- 4-(1- cyclobutyloctahydro- 5H-pyrrolo[3,2- c]pyridin-5-yl)-1-(4- fluorophenyl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E514
I33
503
504


 


E373




methyl 3-cyclobutyl- 1-(4-fluorophenyl)-4- [1-(oxetan-3- yl)octahydro-5H- pyrrolo[3,2-c]pyridin- 5-yl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E514
I33
505
506


 


E374




methyl 3-cyclobutyl- 1-(4-fluorophenyl)-4- [1-(oxan-4- yl)octahydro-5H- pyrrolo[3,2-c]pyridin- 5-yl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E514
I33
533
534


 


E375




methyl 3-cyclobutyl- 4-(4-fluoro[1,4′- bipiperidin]-1′-yl)-1- (4-fluorophenyl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E353
I18
509
510


 


E376




methyl 3-cyclobutyl- 1-(4-fluorophenyl)-4- {4-[(2- methoxyethyl)(methyl) amino]piperidin-1- yl}-1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E353
I18
495
496


 


E377




methyl 3-cyclobutyl- 1-(4-fluorophenyl)-4- [4-(morpholin-4- yl)piperidin-1-yl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
HP19
I3
493
494


 


E378




methyl 4-([1,4′- bipiperidin]-1′-yl)-3- cyclobutyl-1-(4- fluorophenyl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
HP19
I3
491
492


 


E379




methyl 3-cyclobutyl- 1-(4-fluorophenyl)-4- (3-hydroxy-1-oxa-8- azaspiro[4.5]decan-8- yl)-1H-pyrazolo[3,4- b]pyridine-6- carboxylate
HP19
I3
480
481


 


E380




methyl 3-cyclobutyl- 1-(4-fluorophenyl)-4- (3-oxo-1-oxa-8- azaspiro[4.5]decan-8- yl)-1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E379
I23
478
479


 


E381




methyl 3-cyclobutyl- 1-(4-fluorophenyl)-4- [3-(morpholin-4-yl)-1- oxa-8- azaspiro[4.5]decan-8- yl]-1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E380
I18
533
534


 


E382




methyl 3-cyclobutyl- 1-(4-fluorophenyl)-4- {4-[2-(morpholin-4- yl)ethyl]piperidin-1- yl)-1H-pyrazolo[3,4- b]pyridine-6- carboxylate
HP19
I3
521
522


 


E383




methyl 3-cyclobutyl- 4-{4-[2-(4- methylpiperidin-1- yl)ethyl]piperidin-1- yl)-1-phenyl-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
515
516


 


E384




methyl 3-cyclobutyl- 4-[4-(4- cyclopropylpiperazin- 1-yl)piperidin-1-yl]-1- phenyl-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
514
515


 


E385




methyl 3-cyclobutyl- 1-phenyl-4-[4- (propan-2- yl)piperazin-1-yl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
433
434


 


E388




ethyl 3-cyclobutyl-4- [4-(methoxymethyl) piperidin- 1-yl]-1-(2- methoxypyridin-4-yl)- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E168
I4
479
480


 


E389




ethyl 1-(2- chloropyridin-4-yl)-3- cyclobutyl-4-[4- (methoxymethyl) piperidin-1-yl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E168
I4
484- 486
485- 487


 


E390




ethyl 3-cyclobutyl-1- [2-(3,6-dihydro-2H- pyran-4-yl)pyridin-4- yl]-4-[4- (methoxymethyl) piperidin-1-yl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E389
Specific example
531
532


 


E391




ethyl 3-cyclobutyl-4- [4-(methoxymethyl) piperidin-1- yl]-1-[2-(oxan- 4-yl)pyridin-4-yl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E390
Specific example
533
534


 


E392




ethyl 1-tert-butyl-3- cyclobutyl-4-[4- (morpholin-4- yl)piperidin-1-yl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
HP20
I3
469
470


 


E393




ethyl 3-cyclobutyl-4- [4-(morpholin-4- yl)piperidin-1-yl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E392
Specific example
413
414


 


E394




ethyl 3-cyclobutyl-1- (2-methoxypyridin-4- yl)-4-[4-morpholin-4- yl)piperidin-1-yl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E393
I4
520
521


 


E395




ethyl 3-cyclobutyl-1- (3-methylphenyl)-4- [4-(morpholin-4- yl)piperidin-1-yl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E393
I4
503
504


 


E396




ethyl 3-cyclobutyl-1- (3-methoxyphenyl)-4- [4-(morpholin-4- yl)piperidin-1-yl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E393
I4
519
520


 


E397




ethyl 3-cyclobutyl-4- [4-(morpholin-4- yl)piperidin-1-yl]-1- [4- (trifluoromethyl)phenyl]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E393
I4
557
558


 


E398




ethyl 3-cyclobutyl-1- (4-fluoro-3- methylphenyl)-4-[4- (morpholin-4- yl)piperidin-1-yl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E393
I4
521
522


 


E399




ethyl 3-cyclobutyl-4- [4-(morpholin-4- yl)piperidin-1-yl]-1- [3- (trifluoromethyl)phenyl]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E393
I4
557
558


 


E400




ethyl 3-cyclobutyl-4- [4-(morpholin-4- yl)piperidin-1-yl)-1- {2-[(propan-2- yl)oxy]pyridin-4-yl}- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E393
I4
548
549


 


E401




ethyl 1-[2- (benzyloxy)pyridin-4- yl]-3-cyclobutyl-4-[4- (morpholin-4- yl)piperidin-1-yl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E393
I4
596
597


 


E402




ethyl 3-cyclobutyl-1- (2-hydroxypyridin-4- yl)-4-[4-(morpholin-4- yl)piperidin-1-yl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E401
Specific example
506
507


 


E403




ethyl 3-cyclobutyl-1- [2- (difluoromethoxy) pyridin-4-yl]-4-[4- (morpholin-4- yl)piperidin-1-yl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E393
I4
556
557


 


E404




ethyl 3-cyclobutyl-1- (3-fluorophenyl)-4-[4- (morpholin-4- yl)piperidin-1-yl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E393
I4
507
508


 


E405




ethyl 3-cyclobutyl-1- (2,2-difluoro-2H-1,3- benzodioxol-5-yl)-4- [4-(morpholin-4- yl)piperidin-1-yl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E393
I4
569
570


 


E406




ethyl 1-(2- chloropyridin-4-yl)-3- cyclobutyl-4-[4- (morpholin-4- yl)piperidin-1-yl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E393
I4
525- 527
526- 528


 


E407




ethyl 3-cyclobutyl-4- [4-(morpholin-4- yl)piperidin-1-yl]-1- [2-(oxan-4-yl)pyridin- 4-yl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E406
Specific example
574
575


 


E408




methyl 3-cyclobutyl- 4-[4-(ethoxymethyl)- 4-fluoropiperidin-1- yl]-1-phenyl-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02, AMI04
I3
466
467


 


E409




methyl 3-cyclobutyl- 4-{4-fluoro-4-[(2- methoxyethoxy)methyl] piperidin-1-yl}-1- phenyl-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02, AMI05
I3
496
497


 


E410




methyl 3-cyclobutyl- 4-{3-fluoro-3-[(2- methoxyethoxy)methyl] piperidin-1-yl}-1- phenyl-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02, AMI08
I3
496
497


 


E411




methyl 3-cyclobutyl- 4-[4-fluoro-4- (methoxymethyl) piperidin-1- yl]-1-phenyl- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
HP02, AMI07
I3
452
453


 


E412




methyl 3-cyclobutyl- 4-{4-[2-(4- methylpiperidin-1- yl)ethyl]piperidin-1- yl}-1-phenyl-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
515
516


 


E413




methyl 3-cyclobutyl- 1-(4-fluorophenyl)-4- (piperidin-4-yl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
HP19
Specific example
408
409


 


E414




methyl 3-cyclobutyl- 4-[1-(4,4- difluorocyclohexyl) piperidin-4-yl]-1-(4- fluorophenyl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E413
I18
526
527


 


E415




methyl 3-cyclobutyl- 1-(4-fluorophenyl)-4- [1-(propan-2- yl)piperidin-4-yl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E413
I18
450
451


 


E416




methyl 3-cyclobutyl- 1-(4-fluorophenyl)-4- [1-(oxan-4- yl)piperidin-4-yl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E413
I18
492
493


 


E417




methyl 3-cyclobutyl- 1-(4-fluorophenyl)-4- {1-[(oxan-4- yl)methyl]piperidin-4- yl}-1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E413
I18
506
507


 


E418




methyl 3-cyclobutyl- 4-{1-[(2,5- dimethoxyoxolan-3- yl)methyl]piperidin-4- yl}-1-(4- fluorophenyl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E413
I18
552
553


 


E419




methyl 3-cyclobutyl- 1-(4-fluorophenyl)-4- [1-(3,3,3- trifluoropropyl)piperidin- 4-yl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E413
I18
504
505


 


E421




methyl 3-cyclobutyl- 4-[1- (cyclopropylmethyl) piperidin-4-yl]-1-(4- fluorophenyl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E413
I18
462
463


 


E422




ethyl 1-(2- chloropyrimidin-4-yl)- 3-cyclobutyl-4-(4- (morpholin-4- yl)piperidin-1-yl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E393
I5
525
526


 


E424




methyl 3-cyclobutyl- 1-(4-fluorophenyl)-4- (4-methoxy[1,4′- bipiperidin]-1′-yl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
HP19
I3
521
522


 


E425




ethyl 1-cyclohexyl-4- (4-formylphenyl)-3- [(propan-2-yl)oxy]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
ALP36, AMP95
Specific example
435
436


 


E426




ethyl 1-cyclohexyl-4- (4-{[3- (dimethylamino) azetidin-1- yl]methyl}phenyl)-3- [(propan-2-yl)oxy]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E425
I34, Specific example
519
520


 


E427




methyl 3-cyclobutyl- 1-(4-fluorophenyl)-4- [4-(3-fluoropyrrolidin- 1-yl)piperidin-1-yl]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E353
I18
495
496


 


E428




methyl 4-[4-(3- cyanoazetidin-1- yl)piperidin-1-yl]-3- cyclobutyl-1-(4- fluorophenyl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E353
I18
488
489


 


E429




methyl 3-cyclobutyl- 1-(4-fluorophenyl)-4- [4-(3- methoxypyrrolidin-1- yl)piperidin-1-yl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E353
I18
507
508


 


E430




methyl 3-cyclobutyl- 4-(1,4- dioxaspiro[4.5]dec-7- en-8-yl)-1-phenyl-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
Specific example
445
446


 


E431




methyl 3-cyclobutyl- 4-(1,4- dioxaspiro[4.5]decan- 8-yl)-1-phenyl-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E430
Specific example
447
448


 


E432




methyl 3-cyclobutyl- 4-(4-oxocyclohexyl)- 1-phenyl-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E431
Specific example
403
404


 


E433




methyl 3-cyclobutyl- 4-[4-(morpholin-4- yl)cyclohexyl]-1- phenyl-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E432
I18
474
475


 


E434




methyl 3-cyclobutyl- 1-(4-fluorophenyl)-4- {4-[4-(propan-2- yl)piperazin-1- yl]piperidin-1-yl}-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E353
I18
534
535


 


E435




ethyl 1-cyclohexyl-3- [(propan-2-yl)oxy]-4- (4-{[4-(propan-2- yl)piperazin-1- yl]methyl}phenyl)- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E425
I34
547
548


 


E436




ethyl 1-cyclohexyl-4- {4-[(4- methoxypiperidin-1- yl)methyl]phenyl}-3- [(propan-2-yl)oxy]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E425
I34
534
535


 


E437




ethyl 1-cyclohexyl-4- {4-[(5- methylhexahydropyrrolo [3,4-c]pyrrol- 2(1H)- yl)methyl]phenyl}-3- [(propan-2-yl)oxy]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E425
I34
545
546


 


E438




4-{1-cyclohexyl-6- (ethoxycarbonyl)-3- [(propan-2-yl)oxy]- 1H-pyrazolo[3,4- b]pyridin-4- yl}benzoic acid
E425
Specific example
451
452


 


E439




ethyl 4-{4-[5-(tert- butoxycarbonyl) hexahydropyrrolo[3,4- c]pyrrole-2(1H)- carbonyl]phenyl}-1- cyclohexyl-3- [(propan-2-yl)oxy]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E438
I24, Specific example
645
646


 


E440




ethyl 1-cyclohexyl-4- [4-(5- methylhexahydropyrrolo [3,4-c]pyrrole- 2(1H)- carbonyl)phenyl]-3- [(propan-2-yl)oxy]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E438
I24
559
560


 


E441




ethyl 1-cyclohexyl-4- {4-[3- (dimethylamino) azetidine-1- carbonyl]phenyl}-3- [(propan-2-yl)oxy]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E438
I24, Specific example
533
534


 


E442




ethyl 4-(4-{[8-(tert- butoxycarbonyl)-2- oxa-5,8- diazaspiro[3.5]nonan- 5-yl]methyl}phenyl)- 1-cyclohexyl-3- [(propan-2-yl)oxy]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E425
I34
647
648


 


E443




ethyl 1-cyclohexyl-4- {4-[(2-oxa-5,8- diazaspiro[3.5]nonan- 5-yl)methyl]phenyl}- 3-[(propan-2-yl)oxy]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E442
I25
547
548


 


E444




ethyl 1-cyclohexyl-4- {4-[(8-methyl-2-oxa- 5,8- diazaspiro[3.5]nonan- 5-yl)methyl]phenyl}- 3-[(propan-2-yl)oxy]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E443
Specific example
561
562


 


E445




ethyl 4-[4-(4-cyano-1- methylpiperidin-4- yl)phenyl]-1- cyclohexyl-3- [(propan-2-yl)oxy]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
ALP38, AMP 95
Specific example
529
530


 


E460




methyl 3-cyclobutyl- 1-(4-fluorophenyl)-4- {4-[1-(morpholin-4- yl)ethyl]piperidin-1- yl}-1H-pyrazolo[3,4- b]pyridine-6- carboxylate
HP19, 436852- 25-4
I3
521
522


 


E461




methyl 3-cyclobutyl- 1-cyclohexyl-4-[4-(2- methylpyridin-4- yl)piperazin-1-yl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
HP25, 98010- 38-9
I3
488
489


 


E462




methyl 3-cyclobutyl- 1-cyclohexyl-4-{4-[4- (propan-2- yl)piperazin-1- yl]piperidin-1-yl}-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
HP25, 202991- 78-4
I3
522
523


 


E463




methyl 4-[(3S)-4- benzyl-3- methylpiperazin-1-yl]- 3-cyclobutyl-1- cyclohexyl-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
HP25, 511254- 92-57
I3
501
502


 


E464




methyl 4-[(3R)-4- benzyl-3- methylpiperazin-1-yl]- 3-cyclobutyl-1- cyclohexyl-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
HP25, 158848 0-39-0
I3
501
502


 


E465




methyl 3-cyclobutyl- 4-[4-(4- cyclopropylpiperazin- 1-yl)piperidin-1-yl]-1- (4-fluorophenyl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E498
I26, Specific example
517
518


 


E466




methyl 3-cyclobutyl- 4-(9-cyclopropyl-3,9- diazaspiro[5.5]undecan- 3-yl)-1-(4- fluorophenyl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E500
I26
517
518


 


E467




methyl 3-cyclobutyl- 1-(4-fluorophenyl)-4- {4-[(pyrrolidin-1- yl)methyl]piperidin-1- yl}-1H-pyrazolo[3,4- b]pyridine-6- carboxylate
HP19, 683772- 11-5
I3
491
492


 


E468




methyl 3-cyclobutyl- 1-(4-fluorophenyl)-4- {4-[4-(2- methoxyethyl)piperazin- 1-yl]piperidin-1- yl)-1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E498, 6482- 24-2
I27
550
551


 


E469




methyl 3-cyclobutyl- 1-(4-fluorophenyl)-4- [9-(oxetan-3-yl)-3,9- diazaspiro[5.5]undecan- 3-yl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E500, 6704- 31-0
I30, Specific example
533
534


 


E470




methyl 3-cyclobutyl- 1-(4-fluorophenyl)-4- {4-[4-(oxetan-3- yl)piperazin-1- yl]piperidin-1-yl}-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E498, 6704- 31-0
I30
548
549


 


E471




methyl 3-cyclobutyl- 1-(4-fluorophenyl)-4- [(morpholin-4- yl)methyl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
HP19, 936329- 94-1
J13
424
425


 


E472




methyl 3-cyclobutyl- 1-(4-fluorophenyl)-4- [(4-methylpiperazin- 1-yl)methyl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
HP19, 101548- 4-22-6
J13
438
439


 


E473




methyl 1-cyclohexyl- 4-{4-[(morpholin-4- yl)methyl]phenyl}-3- [(propan-2-yl)oxy]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E504, 126834 0-94-8
J13
493
493


 


E474




methyl 1-cyclohexyl- 4-[4-(4- methylpiperazine-1- carbonyl)phenyl]-3- [(propan-2-yl)oxy]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E504, 34352- 59-5
I28, Specific example
519
520


 


E475




methyl 3-cyclobutyl- 1-cyclohexyl-4-[4- (pyridin-4- yl)piperazin-1-yl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
HP25, 1008- 91-9
I3
474
475


 


E476




methyl 3- (cyclobutyloxy)-1- cyclohexyl-4-{4- [(morpholin-4- yl)methyl]phenyl}- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E505, 126834 0-94-8
J13
504
505


 


E477




methyl 1-cyclohexyl- 4-{4-[4- (dimethylamino) piperidine-1- carbonyl]phenyl}-3- [(propan-2-yl)oxy]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E504, 4318- 42-7
I28
548
549


 


E478




methyl 1-cyclohexyl- 4-{4-[(piperidin-1- yl)methyl]phenyl}-3- [(propan-2-yl)oxy]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E504, 126834 0-93-7
J13
491
492


 


E479




methyl 1-cyclohexyl- 4-{4-[(4- methylpiperazin-1- yl)methyl]phenyl}-3- [(propan-2-yl)oxy]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E504, 101548 4-22-6
J13
506
507


 


E480




methyl 1-cyclohexyl- 3-[(propan-2-yl)oxy]- 4-{4-[(pyrrolidin-1- yl)methyl]phenyl}- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E504, 888711- 53-3
J13
477
477


 


E481




methyl 3-cyclobutyl- 1-(4-fluorophenyl)-4- {[4-(methoxymethyl) piperidin-1-yl] methyl}-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
HP19, BF01
J13
466
467


 


E482




methyl 1-cyclohexyl- 4-{4-[(4- cyclopropylpiperazin- 1-yl)methyl]phenyl}- 3-[(propan-2-yl)oxy]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E494
I26
531
532


 


E483




methyl 1-cyclohexyl- 3-[(propan-2-yl)oxy]- 4-{4-[4-(propan-2- yl)piperazin-1- yl]phenyl}-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E504, 4318- 42-7
I29
519
520


 


E484




methyl 1-cyclohexyl- 4-[4-(4- cyclopropylpiperazin- 1-yl)phenyl]-3- [(propan-2-yl)oxy]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E504, 20327- 23-5
I29
517
518


 


E485




methyl 4-(4- cyano[1,4′- bipiperidin]-1′-yl)-3- cyclobutyl-1-(4- fluorophenyl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
HP19, AMI11
I3
516
517


 


E486




methyl 3-cyclobutyl- 1-(4-fluorophenyl)-4- {4-[4- (methoxycarbonyl) piperazin-1-yl]piperidin- 1-yl}-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E498
I31, Specific example
550
551


 


E487




methyl 4-[4-(4- acetylpiperazin-1- yl)piperidin-1-yl]-3- cyclobutyl-1-(4- fluorophenyl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E498
I32, Specific example
534
535


 


E488




methyl 3-cyclobutyl- 1-cyclohexyl-4-{4- [(morpholin-4- yl)methyl]piperidin-1- yl}-1H-pyrazolo[3,4- b]pyridine-6- carboxylate
HP25, 81310- 62-5
I3
495
496


 


E489




methyl 3-cyclobutyl- 1-cyclohexyl-4-{4-[2- (morpholin-4- yl)ethyl]piperidin-1- yl}-1H-pyrazolo[3,4- b]pyridine-6- carboxylate
HP25, 500357- 64-2
I3
509
510


 


E490




methyl 3-cyclobutyl- 1-cyclohexyl-4-[4- (morpholin-4- yl)piperidin-1-yl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
HP25, 53617- 35-9
I3
481
482


 


E491




methyl 3-cyclobutyl- 1-(4-fluorophenyl)-4- {4-[(morpholin-4- yl)methyl]piperidin-1- yl}-1H-pyrazolo[3,4- b]pyridine-6- carboxylate
HP19, 202991- 78-4
I3
507
508


 


E492




methyl 3-cyclobutyl- 1-(4-fluorophenyl)-4- (4-hydroxy[1,4′- bipiperidin]-1′-yl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
HP19, 202991- 78-4
I3
507
508


 


E493




methyl 4-([1,4′- bipiperidin]-1′-yl)-3- cyclobutyl-1-(4- fluorophenyl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
HP19, 202991- 78-4
I3
491
492


 


E494




methyl 1-cyclohexyl- 4-{4-[(piperazin-1- yl)methyl]phenyl}-3- [(propan-2-yl)oxy]- 1H-pyrazolo[3,4- b]pyridine 6 carboxylate
E495
I25
491
492


 


E495




methyl 4-(4-{[4-tert- butoxycarbonyl) piperazin-1- yl]methyl}phenyl)-1- cyclohexyl-3- [(propan-2-yl)oxy]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E504, 936329- 97-4
J13
591
592


 


E498




methyl 3-cyclobutyl- 1-(4-fluorophenyl)-4- [4-(piperazin-1- yl)piperidin-1-yl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E499
I25
492
493


 


E499




methyl 4-{4-[4-(tert- butoxycarbonyl) piperazin-1-yl] piperidin-1- yl}-3-cyclobutyl-1-(4- fluorophenyl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
HP19, 205059- 24-1
I3
592
593


 


E500




methyl 3-cyclobutyl- 4-(3,9- diazaspiro[5.5]undecan- 3-yl)-1-(4- fluorophenyl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E501
I25
477
478


 


E501




tert-butyl 9-[3- cyclobutyl-1-(4- fluorophenyl)-6- (methoxycarbonyl)- 1H-pyrazolo[3,4- b]pyridin-4-yl]-3,9- diazaspiro[5.5]undecane- 3-carboxylate
HP19 173405- 78-2
I3
577
578


 


E502




methyl 1-cyclohexyl- 4-[4-(4- methylpiperazin-1- yl)phenyl]-3-[(propan- 2-yl)oxy]-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E504, 109-01- 3
I29, Specific example
491
492


 


E503




methyl 4-(4- bromophenyl)-1- cyclohexyl-3- hydroxy-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
436088- 86-7 and 608128- 34-3
I1, Specific example
430
431


 


E504




methyl 4-(4- bromophenyl)-1- cyclohexyl-3- [(propan-2-yl)oxy]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E503
I17, Specific example
472
472


 


E505




methyl 4-(4- bromophenyl)-3- (cyclobutyloxy)-1- cyclohexyl-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E503
I17, Specific example
504
505


 


E509




methyl 3-cyclobutyl- 4-[4-(morpholin-4- yl)piperidin-1-yl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
53617- 35-9, 16063- 69-7, 5006- 22-4, 301-01- 2, 630-08- 0
Specific example
399
400


 


E510




methyl 3-cyclobutyl- 1-[3-(difluoromethoxy) phenyl]- 4-[4-(morpholin- 4-yl)piperidin-1-yl]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E509
I7, Specific example
541
542


 


E511




methyl 1-(4- fluorophenyl)-4-(4- methoxy[1,4′- bipiperidin]-1′-yl)-3- [(propan-2-yl)oxy]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
AMP96
Specific example
525
526


 


E513




methyl 4-[1-(tert- butoxycarbonyl) octahydro-5H-pyrrol [3,2-c]pyridin-5-yl]-3- cyclobutyl-1-(4- fluorophenyl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylatee
HP19
I3
549
550


 


E514




methyl 3-cyclobutyl- 1-(4-fluorophenyl)-4- (octahydro-5H- pyrrolo[3,2-c]pyridin- 5-yl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E513
I21A
449
450


 


E515




methyl 3-cyclobutyl- 1-(4-fluorophenyl)-4- (9-methyl-3,9- diazaspiro[5.5]undecan- 3-yl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
HP19, 13323- 45-0
I3
491
492


 


E516




methyl 3-cyclobutyl- 4-[4- (ethoxycarbonyl) piperazin-1-yl]-1-(4- fluorophenyl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
HP19, 12-43- 4
I3
481
482


 


E517




methyl 3-cyclobutyl- 1-(4-fluorophenyl)-4- {4-[(2- methylpropoxy)carbonyl] piperazin-1-yl}- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
HP19, 23672- 96-0
I3
509
510









Method J1: Synthesis of Carboxylic Acids by Saponification of Ester




To the intermediate ester (1 equiv) in THF or in a mixture of THF/methanol or in dioxane/water or in THF/methanol/water at RT is added either aqueous 1 to 2 N sodium hydroxide or lithium hydroxide monohydrate (from 1 to 5 equiv). The reaction mixture is stirred at a temperature ranging from RT to 60° C. for 20 minutes to several days (up to 8 days). The volatiles are removed under reduced pressure, and the resulting mixture is acidified with either aqueous 2-6 N HCl or acetic acid. If a filterable suspension is obtained, the precipitate is collected by filtration, washed with water and dried in vacuo to afford the titled compound which is used as such or further purified either by preparative HPLC or flash chromatography on silica gel. In other cases, the mixture is partitioned between water and either dichloromethane or ethyl acetate. The two phases are separated, and the aqueous phase is optionally neutralized and then extracted either with dichloromethane or ethyl acetate. The combined organic phases are washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford the titled compound which is used as such or further purified either by preparative HPLC or flash chromatography on silica gel.
Illustrative Synthesis of Intermediate A056: 4-(4-Cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid




Intermediate E018 (30.7 g, 60.3 mmol) was dissolved in a mixture of THF/methanol (1/1; 1 L) and 2 N sodium hydroxide (109 mL, 218 mmol) in water was added at RT. The solution was stirred for 1 hour. The volatiles were removed under reduced pressure, and the resulting mixture was diluted with water (300 mL). The aqueous phase was acidified with aqueous 2 N HCl (110 mL), and the precipitate was filtered, washed with water and dried at 40° C. under reduced pressure to give the titled compound.
Illustrative Synthesis of Intermediate A285: 3-cyclobutyl-1-phenyl-4-{4-[(pyrrolidin-1-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid




Methyl 3-cyclobutyl-1-phenyl-4-{4-[(pyrrolidin-1-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylate (18.39 g, 38.8 mmol, E357) was dissolved in a mixture of tetrahydrofuran (100 mL), methanol (50 mL), and water (100 mL). To this mixture was added lithium hydroxide hydrate (4.89 g, 116 mmol). The resulting suspension was heated at 50° C. for 30 minutes. The reaction mixture was cooled to room temperature and neutralized with 6 M aqueous HCl (6 mL) to a pH of 7. To this was then added water in 10 mL portions. After a total of 200 mL of water had been added, a solid formed. The solid was collected by filtration and dried to constant weight in a vacuum oven at 50° C. over 72 hours to give 14.98 g of the titled compound. 1H NMR (400 MHz, pyridine-d5) δ ppm 8.89 (d, J=8.0 Hz, 2H), 7.84 (s, 1H), 7.52 (t, J=7.9 Hz, 2H), 7.25 (t, J=7.5 Hz, 1H), 4.14 (p, J=8.4 Hz, 1H), 3.56 (dd, J=12.2, 3.7 Hz, 2H), 2.86-2.67 (m, 4H), 2.63 (br s, 4H), 2.53-2.42 (m, 4H), 2.10-1.98 (m, 4H), 1.83-1.68 (m, 5H), 1.63-1.48 (m, 2H); MS (ESI+) m/z 460.2 (M+H)+.
Method J1A: Synthesis of Carboxylic Acids by Saponification of Ester




To the ester intermediate (1 equiv) in THF or ethanol or methanol or a mixture of the cited solvents at RT is added either aqueous 1 N or 2 N sodium hydroxide 1 (from 1 to 10 equiv). The reaction mixture is stirred at RT until complete conversion is observed. Sodium hydroxide can be added to allow the full conversion of the starting ester. The volatiles are removed under reduced pressure, and the resulting mixture is acidified with either aqueous 1 N or 2 N HCl. If a filterable suspension is obtained, the precipitate is collected by filtration, washed with water and dried in vacuo to afford the titled compound which is used as such or further purified either by preparative HPLC or flash chromatography on silica gel. In other cases, the mixture is partitioned between a phosphate buffer (pH 6.2) and either dichloromethane or chloroform or a mixture of dichloromethane/isopropanol. The organic phases are separated, dried over MgSO4, filtered and concentrated in vacuo to afford the titled compound which is used as such or further purified either by preparative HPLC or flash chromatography on silica gel.
Illustrative Synthesis of A318a: 3-cyclobutyl-1-(3-methylphenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid




Ester E395 (40 mg, 80 μmol) was dissolved in a mixture of THF/ethanol (1/1; 6 mL) and 1 N sodium hydroxide (0.5 mL, 500 μmol) in water was added at RT. The solution was stirred for 4 hours. Aqueous 1 N HCl (0.5 mL, 500 μmol) and a phosphate buffer were added (pH 6.2). The solvent was partially removed under reduced pressure, and the resulting mixture was extracted twice with chloroform. The combined organic phases were dried over magnesium sulfate, filtered and evaporated under reduced pressure to give the titled compound.
Method J2: Synthesis of Acids




A is either N or CH

A′ is either Re or L1-G3C as described in the Summary

The alkylidene pyruvate (1 to 1.5 equiv) and the aminopyrazole (1 to 1.5 equiv) in acetic acid are stirred under air at temperatures ranging from RT to reflux for 1 h to several days. Alternatively, the alkylidene pyruvate (1 to 1.5 equiv) and the aminopyrazole (1 to 1.5 equiv) in DMF or acetic acid are heated under microwave irradiation at 150° C. for 20 minutes to 2 h followed by stirring under air in an opened flask at temperatures ranging from RT to 90° C. for 1 h to several days with or without dilution of the reaction mixture with a large amount of ethanol or methanol. Then the reaction mixture is filtered, and the solid is washed with solvents, and dried in vacuo to afford the titled compound which is used as such or purified by precipitation, by preparative HPLC or by flash chromatography on silica gel. Alternatively, the reaction mixture is concentrated in vacuo to afford a crude mixture which is used as such or further purified either by precipitation, by preparative HPLC or by flash chromatography on silica gel.
Illustrative Synthesis of Intermediate A002: 3-methyl-4-(4-morpholinophenyl)-1-phenyl-pyrazolo[3,4-b]pyridine-6-carboxylic acid




ALP01 (261 mg, 1 mmol, 1 equiv) and 3-methyl-1-phenyl-1H-pyrazol-5-amine (CAS 1131-18-6, 173 mg, 1 mmol, 1 equiv) were introduced in a sealed tube. DMF (2 mL) was added, and the vial was sealed. The reaction mixture was heated under microwave irradiation at 150° C. for 1 h. Then after cooling down to RT, the vial was opened, diluted with a large amount of ethanol, and stirred vigorously under air at RT overnight. The resulting suspension was filtered. The solid was washed with ethanol, and dried in vacuo to afford the titled compound.
Method J3: Nucleophilic Substitution on the Central Core with Alcohols




To a solution of alcohol (3.0 equiv) in anhydrous THF under nitrogen atmosphere at RT is added 60% sodium hydride in mineral oil (6.0 equiv), and the mixture is stirred at room temperature for 30 minutes. Then the aryl chloride intermediate HP (1.0 equiv) is added, the reaction mixture is stirred at room temperature for 5 minutes, and then heated at reflux for 1 h to 24 h. The reaction mixture is cooled to 0° C., diluted with heptane, quenched with water and acidified with 2 N HCl (6.0 equiv). Volatiles are removed in vacuo. The resulting aqueous residue is filtered, and the solid is washed with water and with a mixture heptane/Et2O 1/1, and dried in vacuo to afford the titled compound which is used as such or purified by silica gel chromatography. Alternatively, the aqueous residue is diluted with dichloromethane. The two phases are separated and the aqueous phase is extracted with dichloromethane. The combined organic phases are washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford the titled compound which is used as such or purified by silica gel chromatography.
Alternatively, to a solution of alcohol (2.0 equiv) in anhydrous DMF is added 1 M potassium tert-butoxide (3-4 equiv), and the mixture is stirred at room temperature for several minutes. Then the aryl chloride intermediate HP (1.0 equiv) is added, and then the reaction mixture is heated at 40-60° C. for 1 h to 24 h. After cooling to ambient temperature, the product can be precipitated from an appropriate solvent or purified chromatographically.
Illustrative Synthesis of Intermediate A148: 3-cyclobutyl-1-phenyl-4-(tetrahydropyran-4-ylmethoxy)pyrazolo[3,4-b]pyridine-6-carboxylic acid




To a solution of tetrahydropyran-4-ylmethanol (CAS: 14774-37-9, 54 mg, 0.457 mmol, 3.0 equiv) in anhydrous THF (1 mL) under nitrogen atmosphere was added 60% sodium hydride in mineral oil (37 mg, 0.915 mmol, 6.0 equiv), and the mixture was stirred at room temperature for 30 minutes. HP10 (50 mg, 0.152 mmol, 1.0 equiv) was added; the reaction mixture was stirred at room temperature for 5 minutes and then heated at reflux for 3 hours. The reaction mixture was cooled to 0° C., diluted with heptane (1 mL), quenched with water (1 mL) and acidified with 2 N HCl (0.46 mL, 6.0 equiv). Volatiles were removed in vacuo. The resulting aqueous suspension was diluted with a mixture heptane/Et2O: 1/1 (1 mL) and filtered. The solid was washed with water and with a mixture heptane/Et2O 1/1 and dried in vacuo. The crude solid was purified by silica gel chromatography (eluent system: DCM/(DCM/MeOH/AcOH/H2O: 90/10/1/1) gradient from 100/0 to 90/10) to give the titled compound.
Illustrative Synthesis of Intermediate A 173: 3-cyclobutyl-4-(3-morpholinopropoxy)-1-phenyl-pyrazolo[3,4-b]pyridine-6-carboxylic acid




3-Morpholinopropan-1-ol (73 mg, 0.50 mmol) was dissolved into anhydrous DMF (830 μL), treated with 1 M KOtBu in THF (830 μL, 0.83 mmol), stirred three minutes, treated further with intermediate HP10 (82 mg, 0.25 mmol), and heated at 50° C. for about an hour. More DMF (570 μL) was added and heating was continued overnight. The mixture was brought to room temperature, diluted with MeCN and filtered with a MeCN rinse. The collected solids were mixed with acetic acid into DMSO, and diluted with water to precipitate solids which were collected by filtration, rinsed with water and dried under vacuum to give the titled compound (65 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.38-8.28 (m, 2H), 7.61-7.52 (m, 2H), 7.41 (s, 1H), 7.36-7.29 (m, 1H), 4.43-4.34 (m, 2H), 4.08-3.98 (m, 1H), 3.62-3.58 (m, 4H), 2.57-2.35 (m, 10H), 2.15-1.89 (m, 4H).
Method J4: Buchwald Coupling on the Central Core




To a degassed solution of the aryl chloride intermediate HP (1.0 equiv) and the amine as free base or hydrochloride salt (1.5 equiv) in anhydrous THF at RT under nitrogen atmosphere in a sealed vial is added XPhos Pd G1 (CAS 1028206-56-5, 0.1 equiv) followed by 1 N LiHMDS in THF (from 3 to 5 equiv). The reaction mixture is purged with nitrogen and the vial is sealed. The reaction mixture is stirred at 100° C. for 1 h to 24 h. Then the reaction mixture is cooled down and volatiles are removed in vacuo. The resulting residue is taken up in dichloromethane and water and acidified with acetic acid. The two phases are separated and the aqueous phase is extracted with dichloromethane. The combined organic layers are washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue is purified by flash chromatography on silica gel to afford the titled compound.
Illustrative Synthesis of Intermediate A216: 3-cyclobutyl-4-[4-(fluoromethyl)-1-piperidyl]-1-phenyl-pyrazolo[3,4-b]pyridine-6-carboxylicacid




To a degassed solution of HP10 (64 mg, 0.194 mmol, 1.0 equiv) and 4-(fluoromethyl)piperidine hydrochloride (CAS 259143-04-9, 45 mg, 0.292 mmol, 1.5 equiv) in anhydrous THF (2 mL) at RT under nitrogen atmosphere in a sealed vial was added XPhos Pd G1 (CAS 1028206-56-5, 14 mg, 0.019 mmol, 0.1 equiv) followed by 1 N LiHMDS in THF (0.97 mL, 0.97 mmol, 5.0 equiv). The reaction mixture was purged with nitrogen, and the vial was sealed. The reaction mixture was stirred at 100° C. overnight. Then the reaction mixture was cooled down and volatiles were removed in vacuo. The resulting residue was taken up in dichloromethane and water and acidified with acetic acid. The two phases were separated, and the aqueous phase was extracted with dichloromethane. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (eluent system: dichloromethane/methanol gradient from 100/0 to 95/5) to afford the titled compound.
Method J5: Buchwald Coupling on the Aryl Linker




R′′=H or C1-C6 alkyl

A=N or CH

LG3=Cl or Br

To a degassed solution of pyridyl chloride (1.0 equiv) and amine (1.5 equiv) in anhydrous THF at RT under nitrogen atmosphere is added 1 N LiHMDS in THF (from 3 to 4.5 equiv) followed by XPhos Pd G1 (CAS 1028206-56-5, 0.1 equiv). The reaction mixture is stirred at room temperature for 1 h to 24 h. The mixture is quenched with acetic acid and diluted with water and dichloromethane. The organic layer is separated, washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo to afford the titled compound which is used as such or further purified by preparative HPLC or by flash chromatography on silica gel. The cross-coupling reaction can be performed on either a carboxylic acid or ester. In some instances, an ester starting material is concomitantly hydrolyzed to the corresponding carboxylic acid product under the reaction conditions.
Illustrative Synthesis of Intermediate A065: 1-cyclohexyl-4-[6-(2,6-dimethylmorpholin-4-yl)-3-pyridyl]-3-isopropyl-pyrazolo[3,4-b]pyridine-6-carboxylic acid




To a degassed solution of A250 (75 mg, 0.188 mmol, 1.0 equiv) and 2,6-dimethylmorpholine (CAS 141-91-3, 32 μL, 0.26 mmol, 1.5 equiv) in anhydrous THF (0.7 mL) at RT under nitrogen atmosphere was added 1 N LiHMDS in THF (765 μL, 0.765 mmol, 4.5 equiv) followed by XPhos Pd G1 (CAS 1028206-56-5, 12.5 mg, 0.017 mmol, 0.1 equiv). The reaction mixture was stirred at room temperature for 1 h. The mixture was quenched with AcOH and diluted with water and dichloromethane. The organic layer was separated, washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (eluent system: dichloromethane/methanol, gradient from 100/0 to 95/5) to afford the titled compound.
Method J6: Nucleophilic Substitution on the R1 Part




A=N or CH

To the intermediate fluoropyridine (1.0 equiv) in anhydrous DMSO is added the amine (from 2.0 to 10.0 equiv) and K2CO3 (from 3.0 to 10 equiv). The reaction mixture is stirred at 100° C. overnight. If the reaction is not complete, additional amine (from 2.0 to 10 equiv) and K2CO3 (from 0 to 10 equiv) are added, and the reaction mixture is stirred at 100° C. until the reaction is finished. Then the reaction mixture is cooled down to RT, diluted with water and extracted with ethyl acetate. The combined organic layers are washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford the titled compound which is used as such or purified by flash chromatography on silica gel.
Illustrative Synthesis of Intermediate A179: 3-isopropyl-4-[4-(methoxymethyl)-1-piperidyl]-1-(2-morpholino-4-pyridyl)pyrazolo[3,4-b]pyridine-6-carboxylic acid




To E147 (144 mg, 0.32 mmol, 1.0 equiv) in anhydrous DMSO (1.5 mL) was added morpholine (56 μL, 0.64 mmol, 2.0 equiv) and K2CO3 (133 mg, 0.96 mmol, 3.0 equiv). The reaction mixture was stirred at 100° C. overnight. Additional morpholine (56 μL, 0.64 mmol, 2.0 equiv) and K2CO3 (133 mg, 0.96 mmol, 3.0 equiv) were added, and the reaction mixture was stirred at 100° C. for 24 h. Then additional morpholine (56 μL, 0.64 mmol, 2.0 equiv) was added again, and the reaction mixture was stirred at 100° C. for 5 days. Then the reaction mixture was cooled down to RT, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (eluent system: dichloromethane/methanol, gradient 100/0 to 95/5 with 0.1% AcOH) to afford the titled compound.
Method J7: Buchwald Coupling on the Phenyl or Heteroaryl Halogen




A=CH, N

To a degassed solution of the aromatic bromide intermediate (1.0 equiv) and the amine as free base or hydrochloride salt (from 1.5 to 2 equiv) in anhydrous THF at RT under nitrogen atmosphere in a sealed vial is added XPhos Pd G1 (CAS 1028206-56-5, 0.1 equiv) followed by 1 N LiHMDS in THF (from 3 to 5 equiv). The reaction mixture is purged with nitrogen, and the vial is sealed. The reaction mixture is stirred at a temperature ranging from RT to 100° C. for 1 h to 3 h. If the reaction is not complete, additional amine (from 1.0 to 3.0 equiv), LiHMDS (from 1.5 to 6.0 equiv) and XPhos Pd G1 (CAS 1028206-56-5, from 0.05 to 0.2 equiv) are added at RT. The reaction mixture is purged again with nitrogen and the vial is sealed. The reaction mixture is stirred at a temperature ranging from RT to 100° C. for 1 h to 3 h. Then the reaction mixture is cooled down and volatiles are removed in vacuo. The resulting residue is taken up in dichloromethane and water and acidified with acetic acid. The two phases are separated, and the aqueous phase is extracted with dichloromethane. The combined organic layers are washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue is purified by flash chromatography on silica gel to afford the titled compound.
Illustrative Synthesis of Intermediate A212: 3-isopropyl-4-(4-methoxy-1-piperidyl)-1-(2-morpholino-4-pyridyl)pyrazolo[3,4-b]pyridine-6-carboxylic acid




To a degassed solution of A257 (22 mg, 0.046 mmol, 1.0 equiv) and morpholine (6 μL, 0.069 mmol, 1.5 equiv) in anhydrous THF (1 mL) at RT under nitrogen atmosphere in a sealed vial was added XPhos Pd G1 (CAS 1028206-56-5, 3 mg, 0.0046 mmol, 0.1 equiv) followed by 1 N LiHMDS in THF (138 μL, 0.138 mmol, 3.0 equiv). The reaction mixture was purged with nitrogen, and the vial was sealed. The reaction mixture was stirred at 100° C. for 1.5 h. Additional morpholine (12 μL, 0.138 mmol, 3.0 equiv), 1 N LiHMDS in THF (276 μL, 0.276 mmol, 6.0 equiv) and XPhos Pd G1 (CAS 1028206-56-5, 6 mg, 0.0092 mmol, 0.2 equiv) were added at RT. The reaction mixture was purged again with nitrogen, and the vial was sealed. The reaction mixture was stirred at 100° C. for 1 h. Then the reaction mixture was cooled down and volatiles were removed in vacuo. The resulting residue was taken up in dichloromethane and water and acidified with acetic acid. The two phases were separated, and the aqueous phase was extracted with dichloromethane. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (eluent system dichloromethane/methanol gradient from 100/0 to 90/10 with 0.1% AcOH) to afford the titled compound.
Method J8: Tandem Methylation and Saponification




60% NaH in mineral oil (6.0 equiv) is added to a solution of an ester/alcohol or a 2-oxo-1,2-dihydropyridin-4-yl/ester (1 equiv) in THF. The reaction mixture is stirred at RT for 5 minutes, and a C1-C6 alkyl halide (6.0 equiv) was added. The reaction mixture was stirred at RT for 1-24 hours and then concentrated. The residue was purified by silica gel chromatography to give the ether/carboxylic acid or the 1-methyl-2-oxo-1,2-dihydropyridin-4-yl/carboxylic acid.
Illustrative Synthesis of Intermediate A 62: 1-cyclohexyl-3-isopropyl-4-[4-(methoxymethyl)-1-piperidyl]pyrazolo[3,4-b]pyridine-6-carboxylic acid




60% NaH in mineral oil (24 mg, 0.60 mmol, 6.0 equiv) was added to a solution of E134 (42 mg, 0.10 mmol) in THF (1 mL). The reaction mixture was stirred at RT for 5 minutes, and methyl iodide (0.037 mL, 0.60 mmol, 6.0 equiv) was added. The reaction mixture was stirred at RT for 16 hours and then concentrated. The residue was purified by silica gel chromatography (DCM/MeOH: 100/0 to 90/10) to give the titled compound.
Method J9: Amide or Carbamate Formation from an Amine




R′′=C1-C6 alkyl or O—C1-C6 alkyl

A heterocyclic amine at either the R2 or R3 positions can be reacted with an acid chloride or chloroformate dissolved is solvents such as dichloromethane, tetrahydrofuran or DMF at 0° C. to ambient temperature over 0.5-4 hours in the presence a tertiary amine base or an inorganic carbonate base. The reaction mixture is extractively worked up and/or purified chromatographically either by flash chromatography or by preparative HPLC.
Illustrative Synthesis of Intermediate A225: 4-[(1-acetyl-4-piperidyl)methoxy]-3-cyclobutyl-1-phenyl-pyrazolo[3,4-b]pyridine-6-carboxylic acid




To A261 as a trifluoroacetic acid salt (0.43 g, 0.83 mmol, 1 equiv) in anhydrous dichloromethane (10 mL) at 0° C. was added triethyl amine (0.69 mL, 4.98 mmol, 6 equiv) followed by acetyl chloride (CAS 75-36-5, 119 μL, 1.66 mmol, 2 equiv). The reaction mixture was stirred at RT for 1 h. The reaction mixture was diluted with dichloromethane and water. The two phases were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (eluent system: dichloromethane/methanol gradient from 100/0 to 95/5) to afford the titled compound.
Illustrative Synthesis of Intermediate A237: 3-cyclobutyl-4-[(1-methoxycarbonyl-4-piperidyl)methoxy]-1-phenyl-pyrazolo[3,4-b]pyridine-6-carboxylic acid




To A261 as a trifluoroacetic acid salt (0.43 g, 0.83 mmol, 1 equiv) in anhydrous dichloromethane (10 mL) at 0° C. was added triethylamine (0.69 mL, 4.98 mmol, 6 equiv) followed by methyl chloroformate (CAS: 79-22-1, 128 μL, 1.66 mmol, 2 equiv). The reaction mixture was stirred at RT for 1 h. The reaction mixture was diluted with dichloromethane and water. The two phases were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was taken up in a mixture of THF (1.5 mL), methanol (1.5 mL) and aqueous 2 M sodium hydroxide (0.17 mL) and stirred at RT for 1.5 h. The mixture was concentrated in vacuo. The residue was diluted with ethyl acetate and water and acidified with 1 M HCl (0.34 mL). The two phases were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford the titled compound which was used as such.
Illustrative Synthesis of Intermediate A249: 1-cyclohexyl-4-[2-(dimethylamino)pyrimidin-5-yl]-3-(1-methoxycarbonylazetidin-3-yl)pyrazolo[3,4-b]pyridine-6-carboxylic acid




Diisopropylethylamine (0.55 mL, 3.12 mmol, 6.0 equiv) and DMAP (13 mg, 0.104 mmol, 0.2 equiv) were added to a solution of A248 (220 mg, 0.52 mmol, 1 equiv) in dichloromethane (2 mL). The mixture was cooled to 0° C. and methyl chloroformate (CAS: 79-22-1, 81 μL, 0.104 mmol, 2.0 equiv) was added. The reaction mixture was warmed up to RT and stirred for 1.5 h. The reaction mixture was partitioned between dichloromethane and water. The two phases were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phase were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC to afford the titled compound.
Method J10: Nucleophilic Substitution on the Central Core with Amines




LG=Cl, OTf

A mixture of the chloride or triflate intermediate HP (1.0 equiv), the amine as free base or hydrochloride salt (from 1 to 10 equiv) and DIPEA (from 1 to 15 equiv) in anhydrous acetonitrile and DMSO or N,N-dimethylacetamide in a sealed tube or a round bottom flask is heated at a temperature ranging from 50 to 130° C. for 1 h to several days (up to 8 days). The reaction mixture is cooled to RT. The resulting residue is either purified by precipitation or by flash chromatography on silica gel to afford the titled compound or alternatively partitioned between either dichloromethane or ethyl acetate and water. The two phases are then separated, and the aqueous phase is extracted with either ethyl acetate or dichloromethane. The combined organic phases are dried, filtered and concentrated in vacuo, and the resulting crude mixture is either used as such or purified by flash chromatography on silica gel to afford the titled compound.
Alternatively, a mixture of the chloride or triflate intermediate HP (1.0 equiv), the amine as free base or hydrochloride salt (from 1 to 10 equiv) and triethylamine (from 1 to 15 equiv) in N,N-dimethylacetamide is heated with microwave irradiation at a temperature ranging from 130 to 150° C. for 5 to 20 min. DBU (1 equiv) was added, and the reaction mixture is again heated with microwave irradiation for 1 to 4 hours at 130 to 150° C. Upon cooling, solids are collected and then precipitated from a solvent such as acetonitrile.
Illustrative Synthesis of Intermediate A081: 3-cyclobutyl-1-phenyl-4-[4-(1-piperidyl)-1-piperidyl]pyrazolo[3,4-b]pyridine-6-carboxylic acid




A suspension of intermediate HP10 (328 mg, 1.0 mmol), 1,4′-bipiperidine (253 mg, 1.50 mmol) and triethylamine (350 μL, 2.5 mmol) in anhydrous DMA (800 μL) was heated in a Biotage® Initiator microwave synthesizer at 150° C. for fifteen minutes. DBU (180 μL, 1.2 mmol) was added, and the reaction mixture was heated with microwave irradiation at 150° C. for one hour and 45 minutes, brought to room temperature, diluted with water (8 mL) and washed with 1:2 EtOAc/MTBE. The aqueous phase was acidified with 3 M aqueous citric acid (400 μL) to precipitate the product, which was collected by filtration, washed with water and dried under vacuum to give the titled compound (423 mg). 1H NMR (400 MHz, DMSO-d6, 120° C.) δ ppm 8.32 (d, J=8.1 Hz, 2H), 7.54-7.48 (m, 2H), 7.32-7.26 (m, 2H), 4.02 (p, J=8.1 Hz, 1H), 3.63-3.58 (m, 2H), 3.00-2.91 (m, 2H), 2.63-2.57 (m, 4H), 2.56-2.41 (m, 5H), 2.16-1.91 (m, 4H), 1.82-1.69 (m, 2H), 1.60-1.51 (m, 4H), 1.48-1.39 (m, 2H).
Illustrative Synthesis of Intermediate A268: 3-cyclobutyl-4-(4-morpholino-1-piperidyl)-1-phenyl-pyrazolo[3,4-b]pyridine-6-carboxylic acid




A suspension of intermediate HP10 (230 mg, 0.70 mmol), 4-(piperidin-4-yl)morpholine (177 mg, 1.05 mmol) and triethylamine (245 μL, 1.76 mmol) in anhydrous DMA (600 μL) was heated in a Biotage® Initiator microwave synthesizer at 140° C. for five minutes. DBU (105 μL, 0.70 mmol) was added, and the reaction mixture was heated with microwave irradiation at 140° C. for three hours, brought to room temperature and filtered through a C18 column (MeOH/H2O). The filtrate was concentrated, and the residual solids were washed with EtOAc, boiled in MeCN and allowed to cool to room temperature. The solid was collected by filtration, rinsed with acetonitrile and dried under vacuum to give the titled compound (305 mg).
1H NMR (400 MHz, DMSO-d6, 90° C.) δ ppm 8.34-8.30 (m, 2H), 7.54-7.48 (m, 2H), 7.30-7.25 (m, 2H), 4.00 (p, J=8.1 Hz, 1H), 3.62-3.58 (m, 4H), 3.56-3.53 (m, 2H), 2.97-2.89 (m, 1H), 2.76-2.68 (m, 1H), 2.56-2.51 (m, 4H), 2.45-2.41 (m, 3H), 2.11-1.94 (m, 4H), 1.85-1.77 (m, 1H), 1.74-1.63 (m, 2H), 1.55-1.44 (m, 1H).
Illustrative Synthesis of Intermediate A270: 3-cyclobutyl-4-[4-(2-morpholinoethyl)-1-piperidyl]-1-phenyl-pyrazolo[3,4-b]pyridine-6-carboxylic acid




A suspension of intermediate HP10 (164 mg, 0.50 mmol), 4-(2-(piperidin-4-yl)ethyl)morpholine (149 mg, 0.75 mmol) and triethylamine (175 μL, 1.26 mmol) in anhydrous DMA (400 μL) was heated in a Biotage® Initiator microwave synthesizer at 150° C. for fifteen minutes. DBU (90 μL, 0.60 mmol) was added, and the reaction mixture was heated by microwave irradiation at 150° C. for one hour, brought to room temperature, diluted with water (8 mL) and concentrated. The residue was slurried in acetonitrile and the solids were collected by filtration to give the titled compound (155 mg).
Illustrative Synthesis of Intermediate A284: 3-cyclobutyl-4-[(3R)-3-(hydroxymethyl)-1-piperidyl]-1-phenyl-pyrazolo[3,4-b]pyridine-6-carboxylic acid




A suspension of 4-chloro-3-cyclobutyl-1-phenyl-pyrazolo[3,4-b]pyridine-6-carboxylic acid (HP10, 164 mg, 0.50 mmol), (R)-piperidin-3-ylmethanol (86 mg, 0.75 mmol) and triethylamine (175 μL, 1.26 mmol) in anhydrous DMA (400 μL) was heated in a microwave reactor at 150° C. for fifteen minutes. DBU (90 μL, 0.60 mmol) was added, and the reaction mixture was heated in the reactor at 150° C. for one hour, brought to room temperature, diluted with water (8 mL), concentrated, and purified by preparative HPLC on a Waters® T3 column (30 mm×100 mm) with a 20 to 100% gradient of acetonitrile in 10 mM aqueous ammonium acetate to give the titled compound (156 mg). 1H NMR (400 MHz, CD2Cl2) δ ppm 7.84 (d, J=8.1 Hz, 2H), 7.21-7.13 (m, 3H), 6.92 (t, J=7.4 Hz, 1H), 3.81 (tt, J=8.5, 8.4 Hz, 1H), 3.54-3.46 (m, 1H), 3.43-3.20 (m, 3H), 2.57-2.24 (m, 6H), 2.04-1.88 (m, 2H), 1.84-1.71 (m, 1H), 1.63-1.49 (m, 3H), 0.95-0.79 (m, 1H).
Illustrative Synthesis of Intermediate A408: 1-(4-fluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid




A suspension of the 4-chloro-1-(4-fluorophenyl)-3-isopropyl-pyrazolo[3,4-b]pyridine-6-carboxylic acid (267 mg, 0.80 mmol, HP11), 4-morpholinopiperidine (204 mg, 1.2 mmol) and triethylamine (280 μL, 2.0 mmol) in anhydrous DMA (700 μL) was heated in a microwave reactor at 150° C. for fifteen minutes. DBU (145 μL, 0.96 mmol) was added, and the reaction mixture was heated at 150° C. two hours, brought to room temperature, diluted with water (7 mL) and washed twice with 1:2 EtOAc/MTBE. The aqueous phase was acidified with aqueous citric acid to pH 5, and the solids were collected by filtration, washed with water and dried under vacuum to give the titled compound.
Illustrative Synthesis of Compound A413: 3-cyclobutyl-4-[4-(hydroxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid




To a solution of HP10 (0.502 g, 1.532 mmol) and 4-piperidinemethanol (0.441 g, 3.83 mmol) in N,N-dimethylacetamide (DMA, 1.5 mL) was added diisopropylethylamine (1.5 mL, 8.59 mmol), and the reaction mixture was then stirred at 150° C. for 12 hours. The reaction mixture was then partitioned between dichloromethane and 1 N HCl. The organic fraction was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified on silica gel, eluting with a gradient of 0-5% MeOH/DCM to give the titled compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.41 (qd, J=12.2, 3.7 Hz, 2H), 1.60 (dtdd, J=13.2, 10.0, 6.2, 3.6 Hz, 1H), 1.83 (dd, J=13.3, 3.4 Hz, 2H), 1.87-2.12 (m, 3H), 2.36 (dtd, J=11.8, 8.5, 3.1 Hz, 2H), 2.51 (dd, J=9.3, 2.3 Hz, 1H), 2.76-2.96 (m, 2H), 3.54 (dd, J=9.4, 6.2 Hz, 2H), 3.94 (p, J=8.4 Hz, 1H), 4.55 (s, 1H), 7.24-7.33 (m, 2H), 7.47-7.58 (m, 2H), 8.30 (d, J=8.0 Hz, 2H).
Method J11: Tandem Nucleophilic Substitution/Saponification




Rm: isopropyl, ethyl

The intermediate ester (1 equiv) is suspended in a mixture of appropriate alcohol for the nucleophilic substitution and THF. 1 N NaOH (from 17 to 19 equiv) is added, and the reaction mixture is stirred at RT or 50° C. until full conversion is observed. 1 N HCl (2 equiv) and a phosphate buffer solution (pH 6.2) are added. The mixture is concentrated under reduced pressure, and the crude residue is partitioned between water and dichloromethane. The organic phase is dried over sodium sulfate, filtered and concentrated under reduced pressure to give the titled compound.
Illustrative Synthesis of A343: 3-cyclobutyl-1-(2-ethoxypyrimidin-4-yl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid




The intermediate ester E422 (30 mg, 57 μmol) was suspended in a mixture of ethanol (8 mL) and THF (3 mL). 1 N NaOH (1 mL, 1 mmol) was added, and the reaction mixture was stirred at RT for 2 hours. 1N HCl (1 mL, 1 mmol) and a phosphate buffer solution (pH 6.2, 5 mL) were added. The mixture was concentrated under reduced pressure, and the crude residue was partitioned between water and dichloromethane. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the titled compound, A343.
Method J12: SNAr on Fluoropyridine




The (6-fluoro-pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid (1 eq) is heated together with the amine (1.05 eq) and DIPEA (1.25 eq) in NMP at 100° C. for 18 hours. Mixture is diluted with EtOAc and water. Isolation of the organic layer and subsequent concentration yields the desired product.
Illustrative Synthesis of Compound A405: 3-Cyclobutyl-1-cyclohexyl-4-[6-(4-cyclopropyl-piperazin-1-yl)-pyridin-3-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid




3-Cyclobutyl-1-cyclohexyl-4-(6-fluoro-pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid (200 mg, 0.51 mmol) was heated together with 1-cyclopropylpiperazine ([20327-23-5], 64 μL, 0.53 mmol) and DIPEA (110 μL, 0.64 mmol) in NMP (2 mL) at 100° C. for 18 hours. The mixture was diluted with EtOAc and water. Isolation of the organic layer and subsequent concentration yielded the titled compound.
Method J13: Suzuki with alkyl-BF3 salts




LG3 is a leaving group suitable for the coupling reaction
Gx is -G3B or -G3B-L1-G3C 
The aryl halide (1 eq) is mixed together with the alkyl-BF3 salt (1.5 eq), Pd(dppf)Cl2.DCM (CAS 95464-05-4, 0.05 eq) and Cs2CO3 (3 eq) in a mixture of THF/H2O (10/1). The mixture is put under N2 atmosphere and heated at 80° C. overnight.
If the method is performed on an ester, the ester can be subsequently hydrolyzed to the acid by the addition of LiOH (2 eq) and heating at 50° C. The titled compound is isolated by acidifying with citric acid till pH=6 and extraction with EtOAc. Concentration, possibly followed by chromatographic purification, gives the titled compound.
Illustrative Synthesis of Compound A361: 3-Cyclobutyl-1-(4-fluoro-phenyl)-4-(4-morpholin-4-yl-piperidin-1-ylmethyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid




HP19 (352 mg, 0.98 mmol) was mixed together with the potassium trifluorido{[4-(morpholin-4-yl)piperidin-1-yl]methyl}borate (426 mg, 1.47 mmol), Pd(dppf)Cl2.DCM (CAS 95464-05-4, 40 mg, 0.05 mmol) and Cs2CO3 (959 mg, 2.94 mmol) in a mixture of THF/H2O (10/1, 5 mL). The mixture was put under a N2 atmosphere and heated at 80° C. overnight. Next, LiOH (82 mg, 2 mmol) was added, and the mixture was heated at 50° C. The titled compound was isolated by acidifying with citric acid till pH=6 and extraction with EtOAc. Concentration, followed by automated preparative chromatographic purification, gave the titled compound.
Method J14: Suzuki and Subsequent Hydrolysis




The arylchloride (1 eq) is mixed with the boronic ester (or acid) (1.5 eq), Pd(dppf)Cl2.DCM (CAS 95464-05-4, 0.1 eq) and DIPEA (3 eq) in a mixture of water/dioxane (1/2). The resulting mixture is stirred at 120° C. for 18 hours. Next, LiOH (2 eq) is added, and the mixture is heated at 40° C. After acidifying with 2 M HCl solution, extraction with EtOAc gives an organic phase that is concentrated to give the titled compound.
Illustrative Synthesis of Compound A365: 3-cyclobutyl-1-cyclohexyl-4-{4-[2-(morpholin-4-yl)ethyl]phenyl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid




Intermediate HP25 (140 mg, 0.40 mmol), 4-(2-morpholinoethyl)phenylboronic acid (142 mg, 0.60 mmol, CAS#1150114-55-8), Pd(dppf)2Cl2 (33 mg, 0.04 mmol) and DIPEA (211 μL, 1.20 mmol) were heated at 120° C. in a mixture of water and dioxane (3 mL, 1:2 water/dioxane). After overnight stirring, LiOH (34 mg, 0.81 mmol) was added, and the resulting mixture was stirred at 40° C. until the hydrolysis was finished. Next, the mixture was diluted with EtOAc and water. After separation, the aqueous phase was acidified with 2 N HCl and subsequently extracted with DCM. The resulting organic phase was dried and concentrated to give the titled compound.
Synthesis of A271: 4-[(3aR,7aS)-1-acetyl-3,3a,4,6,7,7a-hexahydro-2H-pyrrolo[3,2-c]pyridin-5-yl]-3-cyclobutyl-1-phenyl-pyrazolo[3,4-b]pyridine-6-carboxylic acid




Step 1: rac-4-[(3aR,7aS)-1-(tert-butoxycarbonyl)octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl]-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid
Intermediate HP10 (164 mg, 0.50 mmol), the tert-butyl rac-(3aR,7aS)-octahydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (181 mg, 0.80 mmol, CAS#848410-13-9) and diisopropylethylamine (175 μL, 1.0 mmol) were heated in DMSO (350 μL) at 120° C. for a day, brought to room temperature, and partitioned between EtOAc and 2:1 water/brine (600 μL). The aqueous phase was separated and extracted thrice with EtOAc, and the combined organic phases were acidified with TFA, concentrated and chromatographed on silica (0.1% TFA in 1:1 EtOAc/heptane) to give the titled compound (274 mg). 1H NMR (501 MHz, methanol-d4) δ ppm 1.50 (s, 9H), 1.94-2.27 (m, 6H), 2.42-2.51 (m, 2H), 2.52-2.66 (m, 3H), 2.95-3.06 (m, 1H), 3.37-3.58 (m, 5H), 3.94-4.00 (m, 1H), 4.02-4.07 (m, 1H), 7.31-7.35 (m, 1H), 7.44 (s, 1H), 7.50-7.55 (m, 2H), 8.24-8.28 (m, 2H).
Step 2: sodium rac-3-cyclobutyl-4-[(3aR,7aS)-octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylate
rac-4-[(3aR,7aS)-1-(tert-Butoxycarbonyl)octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl]-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid (1.00 g, <1.9 mmol) was dissolved into anhydrous CH2Cl2 (8.0 mL), treated with TFA (2.0 mL), stirred at room temperature for two hours and then concentrated. The residue was redissolved into CH2Cl2, treated with aqueous K2HPO4 and basified to pH 11+ with aqueous NaOH. Brine was added, and the mixture was extracted with 10% MeOH/CH2Cl2. The separated organic phase was dried (Na2SO4), passed through a short column of Na2SO4 and concentrated to give the titled compound (452 mg). 1H NMR (500 MHz, methanol-d4) δ ppm 1.69-1.77 (m, 1H), 1.98-2.21 (m, 5H), 2.40-2.66 (m, 6H), 2.94-3.01 (m, 2H), 3.15-3.3 (m, 3H), 3.32-3.36 (m, 1H), 4.07-4.15 (m, 1H), 7.24-7.28 (m, 1H), 7.38 (s, 1H), 7.47-7.51 (m, 2H), 8.35-8.38 (m, 2H); MS (ESI) m/z 418 (M+H)+.
Step 3: 4-[(3aR,7aS)-1-acetyl-3,3a,4,6,7,7a-hexahydro-2H-pyrrolo[3,2-c]pyridin-5-yl]-3-cyclobutyl-1-phenyl-pyrazolo[3,4-b]pyridine-6-carboxylic acid
Sodium rac-3-cyclobutyl-4-[(3aR,7aS)-octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylate (209 mg, 0.50 mmol) and N-methylmorpholine (220 μL, 2.0 mmol) were suspended in DMF (2.5 mL) and chilled with a water ice bath. A solution of acetyl chloride (50 μL, 0.70 mmol) in dichloromethane (500 μL) was added dropwise, and the mixture was stirred for two minutes before the bath was removed. The cloudy solution was stirred another thirty minutes at room temperature before being diluted with EtOAc and placed directly on silica for chromatography (EtOAc, then 0 to 20% MeOH/MeCN, then 0.1% TFA/19.9% MeOH/80% MeCN) to give rac-4-[(3aR,7aS)-1-acetyloctahydro-5H-pyrrolo[3,2-c]pyridin-5-yl]-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid (236 mg).
The racemate was then subjected to preparative supercritical fluid chromatography set to maintain a maximum back pressure of 100 MPa using a Chiralcel® OJ-H (21×250 mm) column with the sample at a concentration of 10 mg/mL in methanol using 35% methanol in CO2 at a flow rate of 45 mL/minute to provide both enantiomers separately. The first enantiomer eluted (retention time=5.4 minutes), and the second enantiomer eluted (retention time=7.4 minutes) as the titled compound (stereochemistry arbitrarily assigned). 1H NMR (400 MHz, DMSO-d6, 120° C.) δ ppm 1.98 (s, 3H), 1.88-2.22 (m, 6H), 2.40-2.59 (m, 4H), 2.98-3.07 (m, 1H), 3.15-3.19 (m, 1H), 3.31-3.61 (m, 4H), 3.78-3.83 (m, 1H), 3.99-4.13 (m, 2H), 7.27-7.32 (m, 1H), 7.34 (s, 1H), 7.49-7.55 (m, 2H), 8.29-8.35 (m, 2H).
Synthesis of A222: 4-(4-morpholinophenyl)-1-phenyl-pyrazolo[3,4-b]pyridine-6-carboxylic acid




4-(4-Morpholinyl)benzaldehyde (CAS 1204-86-0, 241 mg, 1.26 mmol, 1 equiv), pyruvic acid (CAS 127-17-3, 88 μL, 1.26 mmol, 1 equiv) and 5-amino-1-phenylpyrazole (CAS 826-85-7, 200 mg, 1.26 mmol, 1 equiv) were combined in a sealed tube. Acetic acid (5 mL) was added, and the vial was sealed. The reaction mixture was heated under microwave irradiation at 160° C. for 20 min. The reaction mixture was cooled down and concentrated in vacuo. The resulting residue was purified by preparative HPLC to afford the tiled compound.










List of acids













Int.
Structure
Name
SM
method
MW
Mes





A001




4-(4- methoxyphenyl)- 3-methyl-1- phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
/
96282- 55-5
/
/


 


A002




3-methyl-4-(4- morpholinophenyl)- 1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
ALP01, 1131- 18-6
J2 Specific example
414
415


 


A003




4-(4- methoxyphenyl)- 3-methyl-1-(m- tolyl)pyrazolo[3,4- b]pyridine-6- carboxylic acid
ALP06, 92721- 83-0
J2
373
374


 


A004




1-(3-chloro-4- methyl-phenyl)-4- (4- methoxyphenyl)- pyrazolo[3,4- b]pyridine-6- carboxylic acid
ALP06, 866472- 29-9
J2
407
408


 


A005




4-[4- (dimethylamino) phenyl]-3- isopropyl-1- phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
ALP02, AMP04
J2
400
401


 


A006




4-(4- dimethylaminophenyl)- 3-methyl-1- phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E006
J1
372
373


 


A007




1-(3,5- difluorophenyl)- 3-methyl-4-(4- morpholinophenyl) pyrazolo[3,4- b]pyridine-6- carboxylic acid
ALP01, 1232796 -65-4
J2
450
451


 


A008




1-(3- chlorophenyl)-3- methyl-4-(4- morrpholinophenyl) pyrazolo[3,4- b]pyridine-6- carboxylic acid
ALP01, 40401- 41-0
J2
448
449


 


A009




1-(3- fluorophenyl)-3- methyl-4-(4- morpholinophenyl) pyrazolo[3,4- b]pyridine-6- carboxylic acid
ALP01, 105438- 45-7
J2
432
433


 


A010




1-(3- methoxyphenyl)- 3-methyl-4-(4- morpholinophenyl) pyrazolo[3,4- b]pyridine-6- carboxylic acid
ALP01, 92721- 94-3
J2
444
445


 


A011




3-methyl-4-(4- morpholinophenyl)- 1-[3- (trifluoromethyl) phenyl]pyrazolo[3,4- b]pyridine-6- carboxylic acid
ALP01, 345-07- 3
J2
482
483


 


A012




1-(3,5- dimethylphenyl)- 3-methyl-4-(4- morpholinophenyl) pyrazolo[3,4- b]pyri9dine-6- carboxylic acid
ALP01, 890010- 89-6
J2
442
443


 


A013




3-methyl-4-(4- morpholinophenyl)- 1-[4- (trifluoromethoxy) phenyl]pyrazolo [3,4-b]pyridine-6- carboxylic acid
ALP01, 497141- 59-0
J2
414
415


 


A014




3-methyl-4-(4- morpholinophenyl)- 1-[3- (trifluoromethoxy) phenyl]pyrazolo [3,4-b]pyridine-6- carboxylic acid
ALP01, AMP01
J2
498
499


 


A015




1-(3,4- difluorophenyl)- 3-methyl-4-(4- morpholinophenyl) pyrazolo[3,4- b]pyridine-6- carboxylic acid
ALP01, AMP02
J2
450
451


 


A016




3-methyl-4-(6- morpholino-3- pyridyl)-1- phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E009
J1
415
416


 


A017




4-(4- dimethylaminophenyl)- 3-methyl-1- [3- (trifluoromethyl) phenyl]pyrazolo[3,4- b]pyridine-6- carboxylic acid
ALP02, 345-07- 3
J2
440
441


 


A018




cyclohexyl-4-[2- (dimethylamino) pyrimidin-5-yl]-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
ALP03, AMP23
J2
408
409


 


A019




4-[4- (dimethylamino) phenyl]-3- isopropyl-3-(6- methoxy-3- pyridyl)pyrazolo [3,4-b]pyridine-6- carboxylic acid
ALP02, AMP16
J2
431
432


 


A020




3-isopropyl-4-(4- morpholinophenyl)- 1- tetrahydropyran- 3-yl-pyrazolo[3,4- b]pyridine-6- carboxylic acid
ALP01, AMP25
J2
450
451


 


A021




4-[4-[3- (dimethylamino) azetidin-1- yl]phenyl]-3- methyl-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E011
J1
427
428


 


A022




1-cyclohexyl-3- methyl-4-96- morpholino-3- pyridyl)pyrazolo [3,4-b]pyridine-6- carboxylic acid
ALP05, 56547- 82-1
J2
421
422


 


A023




1-cyclohexyl-4- [2- (dimethylamino) pyrimidin-5-yl]-3- methyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
ALP03, 56547- 82-1
J2
380
381


 


A024




1-[3- (dimethylamino) phenyl]-4-[2- (dimethylamino) pyrimidin-5-yl]-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
ALP03, AMP06
J2
445
446


 


A025




3-isopropyl-4-(2- morpholinopyrimidin- 5-yl)-1- phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
ALP04, AMP04
J2
444
445


 


A026




3-isopropyl-4-(2- morpholinopyrimidin- 5-yl)-1- phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E003
J1
450
451


 


A027




1-cyclopentyl-4- [6- (dimethylamino)- 3-pyridyl]-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
ALP21, AMP26
J2
393
394


 


A028




1-[3- (dimethylamino) phenyl]-3- isopropyl-4-(2- morpholinopyrimidin- 5- yl)pyrazolo[3,4- b]pyridine-6- carboxylic acid
E016
J1
487
488


 


A029




1-[3- (dimethylamino) phenyl]-3- isopropyl-4-(6- morpholino-3- pyridyl)pyrazolo [3,4-b]pyridine-6- carboxylic acid
E015
J1
486
487


 


A030




4-[2- (dimethylamino) pyrimidin-5-yl]-3- isopropyl-1-(3- morpholinophenyl) pyrazolo[3,4- b]pyridine-6- carboxylic acid
ALP03, AMP10
J2
487
488


 


A031




4-[6- (dimethylamino)- 3-pyridyl]-3- isopropyl-1-(3- morpholinophenyl) pyrazolo[3,4- b]pyridine-6- carboxylic acid
ALP21, AMP10
J2
486
487


 


A032




1-cyclohexyl-4- [6- (dimethylamino)- 3-pyridyl]-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
ALP21, AMP23
J2
407
408


 


A033




3-methyl-4-(6- morpholino-3- pyridyl)-1-[3- (trifluoromethyl) phenyl]pyrazolo [3,4-b]pyridine-6- carboxylic acid
ALP05, 345-07- 3
J2
483
484


 


A034




1-(2,4- difluorophenyl)- 3-methyl-4-(6- morpholino-3- pyridyl)pyrazolo [3,4-b]pyridine-6- carboxylic acid
ALP05, 380569- 79-9
J2
451
452


 


A035




1-(2,4- difluorophenyl)- 3-methyl-4-(4- morpholinophenyl) pyrazolo[3,4- b]pyridine-6- carboxylic acid
ALP01, 380569- 79-9
J2
450
451


 


A036




3-methyl-1- phenyl-4-(1- piperidyl)pyrazolo [3,4-b]pyridine- 6-carboxylic acid
E004
J1
336
337


 


A037




3-cyclobutyl-4-(4- morpholinophenyl)- 1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
ALP01, AMP29
J2
454
455


 


A038




1-[3-(azetidin-1- yl)phenyl]-3- isopropyl-4-(4- morpholinophenyl) pyrazolo[3,4- b]pyridine-6- carboxylic acid
E002
J1
497
498


 


A039




3-isopropyl-4-(4- morpholinophenyl)- 1-(3-pyrrolidin- 1- ylphenyl)pyrazolo [3,4-b]pyridine-6- carboxylic acid
E005
J1
511
512


 


A040




1-(4,4- difluorocyclohexyl)- 3-isopropyl-4- (4- morpholinophenyl) pyrazolo[3,4- b]pyridine-6- carboxylic acid
ALP01, AMP24
J2
484
485


 


A041




1-[3-(3,3- dimethylazetidin- 1-yl)phenyl]-3- isopropyl-4-(4- morpholinophenyl) pyrazolo[3,4- b]pyridine-6- carboxylic acid
E012
J1
525
526


 


A042




3-isopropyl-1-(m- tolyl)-4-(1- piperidyl)pyrazolo [3,4-b]pyridine- 6-carboxylic acid
E039
J1
378
379


 


A043




3-isopropyl-1-[3- (3- methoxyazetidin- 1-yl)phenyl]-4-(4- morpholinophenyl) pyrazolo[3,4- b]pyridine-6- carboxylic acid
E008
J1
527
528


 


A044




1-[3-(3- fluoropyrrolidin- 1-yl)phenyl]-3- isopropyl-4-(4- morpholinophenyl) pyrazolo[3,4- b]pyridine-6- carboxylic acid
E013
J1
529
530


 


A045




1-cyclohexyl-3- isopropyl-4-[6- [methyl (tetrahydropyran-4- yl)amino]-3- pyridyl]pyrazolo [3,4-b]pyridine-6- carboxylic acid
E014
J1
477
478


 


A046




4-(4- acetamidophenyl)- 1-cyclohexyl-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E021
J1
420
421


 


A047




3-isopropyl-1-[3- [2- methoxyethyl (methyl)amino]phenyl]- 4-(4- morpholinophenyl) pyrazolo[3,4- b]pyridine-6- carboxylic acid
A242
J7
529
530


 


A048




4-[4-(4-cyano-1- piperidyl)phenyl]- 1-[3- (dimethylamino) phenyl]-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E023
J1
508
509


 


A049




1-[3- (dimethylamino) phenyl]-3- isopropyl-4-[4-[2- methoxyethyl (methyl)amino]phenyl] pyrazolo[3,4- b]pyridine-6- carboxylic acid
E024
J1
487
488


 


A050




4-[6-(4-cyano-1- piperidyl)-3- pyridyl]-1-[3- (dimethylamino) phenyl]-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E025
J1
509
510


 


A051




1-[3- (dimethylamino) phenyl]-3- isopropyl-4-[6-[2- methoxyethyl (methyl)amino]-3- pyridyl]pyrazolo [3,4-b]pyridine-6- carboxylic acid
E026
J1
488
489


 


A052




4-[6-(4-cyano-1- piperidyl)-3- pyridyl]-3- isopropyl-1-(3- morpholinophenyl) pyrazolo[3,4- b]pyridine-6- carboxylic acid
E027
J1
551
552


 


A053




3-isopropyl-4-[6- [2- methoxyethyl (methyl)amino]-3- pyridyl]-1-(3- morpholinophenyl) pyrazolo[3,4- b]pyridine-6- carboxylic acid
E028
J1
530
531


 


A054




1-cyclohexyl-4- [6-(3,3- difluoropyrrolidin- 1-yl)-3-pyridyl]- 3-isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
A250
J5
469
470


 


A055




3-cyclobutyl-4-[6- [2- methoxyethyl (methyl)amino]-3- pyridyl]-1- phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E017
J1
457
458


 


A056




4-[6-(4-cyano-1- piperidyl)-3- pyridyl]-3- cyclobutyl-1- phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E018
J1 Specific example
478
479


 


A057




3-cyclobutyl-4-[6- [methyl (tetrahydropyran-4- yl)amino]-3- pyridyl]-1- phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E019
J1
483
484


 


A058




3-cyclobutyl-4-[4- [2- methoxyethyl(methyl) amino]phenyl]- 1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E020
J1
456
457


 


A059




4-[4-(4-cyano-1- piperidyl)phenyl]- 1-cyclohexyl-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E022
J1
471
472


 


A060




3-isopropyl-4-[6- [methyl (tetrahydropyran-4- yl)amino]-3- pyridyl]-1-(3- morpholinophenyl) pyrazolo[3,4- b]pyridine-6- carboxylic acid
E029
J1
556
557


 


A061




3-isopropyl-4-[4- [2- methoxyethyl (methyl)amino]phenyl]- 1-(3- morpholinophenyl) pyrazolo[3,4- b]pyridine-6- carboxylic acid
E030
J1
529
530


 


A062




1-[3- (dimethylamino) phenyl]-3- isopropyl-4-[6- [methyl (tetrahydropyran-4- yl)amino]-3- pyridyl]pyrazolo[3,4- b]pyridine-6- carboxylic acid
E031
J1
514
515


 


A063




3-isopropyl-4-(3- methoxy-1- piperidyl(-1-(m- tolyl)pyrazolo[3,4- b]pyridine-6- carboxylic acid
E088
J1
408
409


 


A064




3-isopropyl-4-(4- methoxy-1- piperidyl)-1-(m- tolyl)pyrazolo[3,4- b]pyridine-6- carboxylic acid
E048
J1
408
409


 


A065




1-cyclohexyl-4- [6-(2,6- dimethylmorpholin- 4-yl)-3- pyridyl]-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
A250
J5 Specific example
477
478


 


A066




1-cyclohexyl-4- [6-(2,2- dimethylmorpholin- 4-yl)-3- pyridyl]-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
A250
J5
477
478


 


A067




4-[2-(4-cyano-1- piperidyl)pyrimidin- 5-yl]-1-[3- (dimethylamino) phenyl]-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
A034
J1
510
511


 


A068




1-[3- (dimethylamino) phenyl]-3- isopropyl-4-[2- [methyl (tetrahydropyran-4- yl)amino]pyrimidin- 5- yl]pyrazolo[3,4- b]pyridine-6- carboxylic acid
E032
J1
515
516


 


A069




3-isopropyl-4-(4- morpholinophenyl)- 1-(2- morpholino-4- pyridyl)pyrazolo [3,4-b]pyridine-6- carboxylic acid
E066
J1
528
529


 


A070




4-[6-(4-cyano-4- methyl-1- piperidyl)-3- pyridyl]-1- cyclohexyl-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
A250
J5
486
487


 


A071




4-[2-(4-cyano-1- piperidyl) pyrimidin-5-yl]-3- isopropyl-1-(3- morpholinophenyl) pyrazolo[3,4- b]pyridine-6- carboxylic acid
E037
J1
552
553


 


A072




1-[3- (dimethylamino) phenyl]-3- isopropyl-4-[4- [methyl (tetrahydropyran-4- yl)amino]phenyl] pyrazolo[3,4- b]pyridine-6- carboxylic acid
E035
J1
513
514


 


A073




3-isopropyl-4-[4- [methyl (tetrahy7dropyran-4- yl)amino]phenyl]- 1-(3- morpholinophenyl) pyrazolo[3,4- b]pyridine-6- carboxylic acid
E036
J1
555
556


 


A074




3-isopropyl-4-[20 methoxyethyl (methyl)amino]-1-(m- tolyl)pyrazolo[3,4- b]pyridine-6- carboxylic acid
E094
J1
382
383


 


A075




4-[4-[3- (dimethylamino) pyrrolidin-1- yl]phenyl]-3- methyl-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E038
J1
441
442


 


A076




4-[4-(4-cyano-1- piperidyl)phenyl]- 3-cyclobutyl-1- cyclohexyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E040
J1
483
484


 


A077




4-[6-(4-cyano-1- piperidyl)-3- pyridyl]-3- cyclobutyl-1- cyclohexyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E041
J1
484
485


 


A078




4-(4- acetamidophenyl)- 1-(3,5- difluorophenyl)- 3-(1- methoxycarbonyl azetidin-3- yl)pyrazolo[3,4- b]pyridine-6- carboxylic acid
E042
J1
521
522


 


A079




1-cyclohexyl-4- [6-(3-fluoro-1- piperidyl)-3- pyridyl]-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
A250
J5
465
466


 


A080




1-cyclohexyl-3- isopropyl-4-[6-(3- methoxypyrrolidin- 1-yl)-3- pyridyl]pyrazolo [3,4-b]pyridine-6- carboxylic acid
A250
J5
463
464


 


A081




3-cyclobutyl-1- phenyl-4-[4-(1- piperidyl)-1- piperidyl]pyrazolo [3,4-b]pyridine- 6-carboxylic acid
HP10
J10 Specific example
459
460


 


A082




3-isopropyl-4-[4- (methoxyethyl)- 1-piperidyl]-1-(m- tolyl)pyrazolo[3,4- b]pyridine-6- carboxylic acid
E082
J1
422
423


 


A083




3-isopropyl-4-[4- (2-methoxyethyl)- 1-piperidyl]-1-(m- tolyl)pyrazolo[3,4- b]pyridine-6- carboxylic acid
E087
J1
436
437


 


A084




4-[2-(4-cyano-1- piperidyl)pyrimidin- 5-yl]-1- cyclohexyl-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E049
J1
473
474


 


A085




1-cyclohexyl-3- isopropyl-4-[2- [methyl (tetrahydropyran-4- yl)amino]pyrimidin-5- yl]pyrazolo[3,4- b]pyridine-6- carboxylic acid
E051
J1
478
479


 


A086




1-cyclohexyl-3- isopropyl-4-[2-[2- methoxyethyl (methyl)amino] pyrimidin-5- yl]pyrazolo[3,4- b]pyridine-6- carboxylic acid
E050
J1
452
453


 


A087




3-isopropyl-4-[4- [2- methoxyethyl (methyl)amino]phenyl]- 1-(3-pyrrolidin- 1- ylphenyl)pyrazolo [3,4-b]pyridine-6- carboxylic acid
E045
J1
513
514


 


A088




1-(3,4- difluorophenyl)- 3-isopropyl-4-(4- morpholinophenyl) pyrazolo[3,4- b]pyridine-6- carboxylic acid
E057
J1
478
479


 


A089




3-isopropyl-4-(4- morpholinophenyl)- 1-(6- morpholino-2- pyridyl)pyrazolo [3,4-b]pyridine-6- carboxylic acid
E058
J1
528
529


 


A090




3-isopropyl-4-[4- [methy (tetrahydropyran-4- yl)amino]phenyl]- 1-(3-pyrrolidin-1- ylphenyl)pyrazolo [3,4-b]pyridine-6- carboxylic acid
E046
J1
539
540


 


A091




3-cyclobutyl-4-[4- [methy (tetrahydropyran-4- yl)amino]phenyl]- 1-(3-pyrrolidin-1- ylphenyl)pyrazolo [3,4-b]pyridine-6- carboxylic acid
E047
J1
551
552


 


A092




3-isopropyl-4-(4- methylsulfonyl-1- piperidyl)-1-(m- tolyl)pyrazolo[3,4- b]pyridine-6- carboxylic acid
E089
J1
456
457


 


A093




4-[6-(4-cyano-1- piperidyl)-3- pyridyl]-3- isopropyl-1-[3- (trifluoromethyl) phenyl]pyrazolo[3,4- b]pyridine-6- carboxylic acid
E052
J1
534
535


 


A094




4-[4-(4-cyano-1- piperidyl)phenyl]- 3-isopropyl-1-[3- (trifluoromethyl) phenyl]pyrazolo [3,4-b]pyridine-6- carboxylic acid
E065
J1
533
534


 


A095




3-isopropyl-1-(m- tolyl)-4-(8-oxa-3- azaspiro[4.5]decan-3- yl)pyrazolo[3,4- b]pyridine-6- carboxylic acid
E095
J1
434
435


 


A096




1-cyclohexyl-3- isopropyl-4-(4- methoxy-1- piperidyl)pyrazolo [3,4-b]pyridine- 6-carboxylic acid
E076
J1
400
401


 


A097




1-[6- (dimethylamino)- 2-pyridyl]-3- isopropyl-4-(4- morpholinophenyl) pyrazolo[3,4- b]pyridine-6- carboxylic acid
E053
J1
486
487


 


A098




3-isopropyl-4-(4- morpholinophenyl)- 1-[3- (trifluoromethoxy) phenyl]pyrazolo [3,4-b]pyridine-6- carboxylic acid
E054
J1
526
527


 


A099




4-(2,2-difluoro-6- azaspiro[2.4]heptan- 6-yl)-3- isopropyl-1-(m- tolyl)pyrazolo[3,4- b]pyridine-6- carboxylic acid
E075
J5
426
427


 


A100




4-[6-[bis(2- methoxyethyl) amino]-3-pyridyl]-1- cyclohexyl-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
A250
J5
495
496


 


A101




1-cyclohexyl-3- isopropyl-4-[6- [methyl (tetrahydrofuran-3- yl)amino]-3- pyridyl]pyrazolo [3,4-b]pyridine-6- carboxylic acid
A250
J1
463
464


 


A102




1-(4- fluorophenyl)-3- isopropyl-4-[2- [methyl (tetrahydropyran-4- yl)amino]pyrimidin- 5- yl]pyrazolo[3,4- b]pyridine-6- carboxylic acid
E064
J1
490
491


 


A103




4-(2,6-difluoro-4- methoxy-phenyl)- 1-(3-fluoro-5- methoxy-phenyl)- 3-methyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E059
J1
443
444


 


A104




4-[4-(4-cyano-1- piperidyl)phenyl]- 1-(3,5- difluorophenyl)- 3-isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E060
J1
501
502


 


A105




4-[4-(4-cyano-1- piperidyl)phenyl]- 1-(3- fluorophenyl)-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E061
J1
483
484


 


A106




3-isopropyl-4-[4- [2- methoxyethyl (methyl)amino]phenyl]- 1-[3- (trifluoromethyl) phenyl]pyrazolo[3,4- b]pyridin-6- carboxylic acid
E062
J1
512
513


 


A107




3-isopropyl-4-[6- [methyl (tetrahydropyran-4- yl)amino]-3- (trifluoromethyl) phenyl]pyrazolo [3,4-b]pyridine-6- carboxylic acid
E063
J1
539
540


 


A108




4-[2-(4-cyano-1- piperidyl)pyrimidin- 5-yl]-1-(2,4- difluorophenyl)- 3-isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E068
J1
503
504


 


A109




4-[6-(4-cyano-1- pipeidyl)-3- pyridyl]-1-(2,4- difluorophenyl)- 3-isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E069
J1
502
503


 


A110




4-[4-(4-cyano-1- piperidyl)phenyl]- 1-(2,4- difluorophenyl)- 3-isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E070
J1
501
502


 


A111




1-[3- (dimethylamino) phenyl]-3- isopropyl-4-(1- piperidyl)pyrazolo [3,4-b]pyridine- 6-carboxylic acid
E083
J1
407
408


 


A112




4-(4-cyano-1- piperidyl)-1-[3- (dimethylamino) phenyl]-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E086
J1
432
433


 


A113




1-[3- (dimethylamino) phenyl]-3- isopropyl-4-(4- methoxy-1- piperidyl)pyrazolo [3,4-b]pyridine- 6-carboxylic acid
E081
J1
437
438


 


A114




3-(1- methylcyclobutyl)- 4-(4- morpholinophenyl)- 1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E067
J1
468
469


 


A115




4-[4- (fluoromethyl)-1- piperidyl]-3- isopropyl-1-(m- tolyl)pyrazolo[3,4- b]pyridine-6- carboxylic acid
HP16
J4
410
411


 


A116




3-cyclobutyl-4-(4- methoxy-1- piperidyl)-1- phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E071
J1
406
407


 


A117




4-[6-(4-cyano-1- piperidyl)-3- pyridyl]-3- isopropyl-1- tetrahydropyran- 3-yl-pyrazolo[3,4- b]pyridine-6- carboxylic acid
E073
J1
474
475


 


A118




3-cyclobutyl-4-[4- (2-oxo-2- pyrrolidin-1-yl- ethoxy)-1- piperidyl]-1- phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E080
J1
503
504


 


A119




1-[3- (dimethylamino) phenyl]-3- isopropyl-4-[4- (methoxymethyl)- 1- piperidyl]pyrazolo [3,4-b]pyridine- 6-carboxylic acid
E072
J1
451
452


 


A120




4-[6-(4-cyano-1- piepridyl)-3- pyridyl]-3- isopropyl-1-(2- pyrrolidin-1-yl-4- pyridyl)pyrazolo [3,4-b]pyridine-6- carboxylic acid
E084
J1
536
537


 


A121




3-cyclobutyl-4-(4- isopropoxy-1- piperidyl)-1- phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E077
J1
434
435


 


A122




3-cyclobutyl-4-[3- (methoxymethyl)- 1-piperidyl]-1- phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E079
J1
420
421


 


A123




3-isopropoxy-4- (4- morpholinophenyl)- 1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E090
J1
458
459


 


A124




1-(4- fluorophenyl)-3- isopropyl-4-[4- (methoxymethyl)- 1- piperidyl]pyrazolo [3,4-b]pyridine- 6-carboxylic acid
E092
J1
426
427


 


A125




4-[4-(4-cyano-1- piperidyl)phenyl]- 3-isopropyl-1-(2- pyrrolidin-1-yl-4- pyridyl)pyrazolo [3,4-b]pyridine-6- carboxylic acid
E093
J1
535
536


 


A126




1-(4- fluorophenyl)(-3- isopropyl-4-(4- methoxy-1- piperidyl)pyrazolo [3,4-b]pyridine- 6-carboxylic acid
E091
J1
412
413


 


A127




4-(4-butoxy-1- piperidyl)-1-(4- fluorophenyl)-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E096
J1
454
455


 


A128




1-(4- fluorophenyl)-4- (4-isobutoxy-1- piperidyl)-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E098
J1
454
455


 


A129




1-(4- fluorophenyl)-3- isopropyl-4-(4- methoxy-4- methyl-1- piperidyl)pyrazolo [3,4-b]pyridine- 6-carboxylic acid
E097
J1
426
427


 


A130




1-(4-fluorophenyl)-3- isopropyl-4-(3- oxa-7- azaspiro[3.5]nonan- 7- yl)pyrazolo[3,4- b]pyridine-6- carboxylic acid
E099
J1
424
425


 


A131




4-[3- (difluoromethyl)- 1-piperidyl]-1-(4- fluorophenyl)-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E100
J1
432
433


 


A132




1-(4- fluorophenyl)-3- isopropyl-4-(8- oxa-2- azaspiro[3.5]nonan- 2- yl)pyrazolo[3,4- b]pyridine-6- carboxylic acid
E101
J1
424
425


 


A133




1-(4- fluorophenyl)-3- isopropyl-4-(4- oxa-8- azaspiro[4.5]decan- 8- yl)pyrazolo[3,4- b]pyridine-6- carboxylic acid
E102
J1
438
439


 


A134




3-cyclobutyl-4-[4- (2-methoxyethyl)- 1-piperidyl]-1- phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E104
J1
434
435


 


A135




4-(2- azaspiro[3.4]octan- 2-yl)-3- cyclobutyl-1- phenyl- pyrazolo[3,4- b]pyridiune-6- carboxylic acid
E105
J1
402
403


 


A136




3-cyclobutyl-4-[4- (methoxymethyl)- 1-piperidyl]-1- phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E106
J1
420
421


 


A137




4-(3- azabicyclo[3.1.0] hexan-3-yl)-3- cyclobutyl-1- phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E107
J1
374
375


 


A138




3-cyclobutyl-4- (cyclohexylmethoxy)- 1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
HP10
J3
405
406


 


A139




3-cyclobutyl-1- phenyl-4-(1- piperidyl)pyrazolo [3,4-b]pyridine- 6-carboxylic acid
E103
J1
376
377


 


A140




4-(2- azaspiro[3.5]nonan- 2-yl)-3- cyclobutyl-1- phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E115
J1
416
417


 


A141




4-(4-cyano-1- piperidyl)-3- cyclobutyl-1- phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E114
J1
401
402


 


A142




3-cyclobutyl-4-(4- methylsulfonyl-1- piperidyl)-1- phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E113
J1
454
455


 


A143




3-isopropyl-4-(4- methoxy-1- piperidyl)-1-(2- pyrrolidin-1-yl-4- pyridyl)pyrazolo [3,4-b]pyridine-6- carboxylic acid
E110
J1
464
465


 


A144




4-[6-(4-cyano-1- piperidyl)-3- pyridyl]-3- cyclobutyl-1-(2- pyrrolidin-1-yl-4- pyridyl)pyrazolo [3,4-b]pyridine-6- carboxylic acid
E112
J1
548
549


 


A145




3-cyclobutyl-1- phenyl-4-(2- tetrahydropyrazn- 4- ylethoxy)pyrazolo [3,4-b]pyridine-6- carboxylic acid
HP10
J3
421
422


 


A146




3-cyclobutyl-4- [(2S)-2-fluoro-2- tetrahydropyran- 4-yl-ethoxy]-1- phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
HP10, ALC01
J3
439
440


 


A147




4-[6-(4-cyano-1- piperidyl)-3- pyridyl]-3- cyclobutyl-1-(2- morpholino-4- pyridyl)pyrazolo [3,4-b]pyridine-6- carboxylic acid
E121
J1
564
565


 


A148




3-cyclobutyl-1- phenyl-4- (tetrahydropyran- 4- ylmethoxy)pyrazolo [3,4-b]pyridine- 6-carboxylic acid
HP10
J3 Specific example
407
408


 


A149




3-cyclobutylo-4-[3- (methoxymethyl) azetidin-1-yl]-1- phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E116
J1
392
393


 


A150




4-(7- azaspiro[2.5]octan- 7-yl)-3- cyclobutyl-1- phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E125
J1
402
403


 


A151




4-[6-(4-cyano-1- piperidyl)-3- pyridyl]-3-(3,3- difluorocyclobutyl)- 1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E118
J1
514
515


 


A152




4-[6-(4- cyanopiperidin-1- yl)pyridin-3-yl]- 3-[(1s,3s)-3- methoxycyclobutyl]- 1-phenyl-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E117
J1
508
509


 


A153




3-cyclobutyl-4-[2- methoxymethyl (methyl)amino]-1- phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E126
J1
380
381


 


A154




3-cyclobutyl-4- (2,2-difluoro-6- azaspiro[2.4]heptan- 6-yl)-1- phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E122
J1
424
425


 


A155




3-cyclobutyl-4-(9- oxa-2- azaspiro[3.5]nonan- 2-yl)-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E123
J1
418
419


 


A156




3-cyclobutyl-4-(7- oxa-2- azaspiro[3.5]nonan- 2-yl)-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E124
J1
418
419


 


A157




4-(6- azaspiro[3.3]heptan- 6-yl)-3- cyclobutyl-1- phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E128
J1
388
389


 


A158




4-[4- (benzyloxymethyl)- 1-piperidyl]-3- cyclobutyl-1- phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E127
J1
496
497


 


A159




3-cyclobutyl-4- {[(1s,4s)-4- methoxycyclohexyl] oxy}-1-phenyl- 1H-pyrazolo[3,4- b]pyridine-6- carboxylic acid
HP10
J3
421
422


 


A160




3-cyclobutyl-4- {[(1r,4r)-4- methoxycyclohexyl] oxy}-1-phenyl- 1H-pyrazolo[3,4- b]pyridine-6- carboxylic acid
HP10
J3
421
422


 


A161




4-[6-(4-cyano-1- piperidyl)-3- pyridyl]-3-(3,3- dimethylcyclobutyl)- 1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E119
J1
506
507


 


A162




1-cyclohexyl-3- isopropyl-4-[4- (methoxymethyl)- 1- piperidyl]pyrazolo [3,4-b]pyridine- 6-carboxylic acid
E134
J8 Specific example
414
415


 


A163




4-[6-(4-cyano-1- piperidyl)-3- pyridyl]-3-(3- fluorocyclobutyl)- 1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid (cis)
A258
Separation by prep HPLC
496
497


 


A164




4-[6-(4-cyano-1- piperidyl)-3- pyridyl]-3-(3- fluorocyclobutyl)- 1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid trans
A258
Separation by prep HPLC
496
497


 


A165




3-cyclobutyl-4- [(2R)-2-fluoro-2- tetrahydropyran- 4-yl-ethoxy]-1- phenyl pyrazolo[3,4- b]pyridine-6- carboxylic acid
HP10, ALC02
J3
439
440


 


A166




3-cyclobutyl-4- [(3,3- difluorocyclopentyl) methoxy]-1- phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
HP10
J3
427
428


 


A167




3-cyclobutyl-4-[2- (1,1-dioxo-1,4- thiazinan-4- yl)ethoxy]-1- phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
HP10
J3
470
471


 


A168




4-[6-(4-cyano-1- piperidyl)-3- pyridyl]-3- isopropyl-1-(2- morpholino-4- pyridyl)pyrazolo [3,4-b]pyridine-6- carboxylic acid
E138
J1
552
553


 


A169




1-(4- fluorophenyl)-3- isopropyl-4-[4-(1- methoxy-1- methyl-ethyl)-1- piperidyl]pyrazolo [3,4-b]pyridine- 6-carboxylic acid
E136
J8
454
455


 


A170




3-cyclobutyl-4-[4- [(1S)-2- (dimethylamino)- 1-fluoro-ethyl]-1- piperidyl]-1- phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E135
J1
465
466


 


A171




3-cyclobutyl-4- [(3,3-difluoro-1- methyl- cyclobutyl)methoxy]- 1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
HP10
J3
427
428


 


A172




4-[(1-acetyl-4- fluoro-4- piperidyl)methoxy]- 3-cyclobutyl-1- phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
HP10
J3
466
467


 


A173




3-cyclobutyl-4-(3- morpholinopropoxy)- 1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
HP10
J3 Specific example
436
437


 


A174




3-cyclobutyl-4- [(3-methyloxetan- 3-yl)methoxy]-1- phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
HP10
J3
393
394


 


A175




3-cyclobutyl-4-[4- (1-methoxyethyl)- 1-piperidyl]-1- phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E143
J8
434
435


 


A176




3-cyclobutyl-1- phenyl-4-[4- (2,2,2-trifluoro-1- methoxy-1- methyl-ethyl)-1- piperidyl]pyrazolo [3,4-b]pyridine- 6-carboxylic acid
E144
J8
502
503


 


A177




4-[6-[bis(2- methoxyethyl)amino]- 3-pyridyl]-3- cyclobutyl-1- phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E145
J1
501
502


 


A178




4-[6-[bis(2- methoxyethyl)amino]- 3-pyridyl]-3- isopropyl-1-(2- morpholino-4- pyridyl)pyrazolo [3,4-b]pyridine-6- carboxylic acid
E149
J1
575
576


 


A179




3-isopropyl-4-[4- (methoxymethyl)- 1-piperidyl]-1-(2- morpholino-4- pyridyl)pyrazolo [3,4-b]pyridine-6- carboxylic acid
E147
J6 Specific example
494
495


 


A180




3-cyclobutyl-4-[4- methoxy-4- (methoxymethyl)- 1-piperidyl]-1- phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E146
J8
450
451


 


A181




1- (cyclobutylmethyl)- 3-isopropyl-4- [4- (methoxymethyl)- 1- piperidyl]pyrazolo [3,4-b]pyridine- 6-carboxylic acid
E154
J1
400
401


 


A182




1-isobutyl-3- isopropyl-4-[4- (methoxymethyl)- 1- piperidyl]pyrazolo [3,4-b]pyridine- 6-carboxylic acid
E155
J1
388
389


 


A183




4-[6-(4- cyanopiperidin-1- yl)pyridin-3-yl]- 3-[(1r,3r)-3- methylcyclobutyl]- 1-phenyl-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E151
J1
492
493


 


A184




3-[(1-tert- butoxycarbonyl- 4-piperidyl)oxy]- 4-[6-(4-cyano-1- piperidyl)-3- pyridyl]-1- phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E152
J1
623
624


 


A185




3-isopropyl-4-[4- (methoxymethyl)- 1-piperidyl]-1-(2- morpholinopyrimidin- 4- yl)pyrazolo[3,4- b]pyridine-6- carboxylic acid
E160
J1
495
496


 


A186




4-[6-(4-cyano-1- piperidyl)-3- pyridyl]-1- phenyl-3- tetrahydrofuran-3- yloxy- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E159
J1
510
511


 


A187




4-[6-(4-cyano-1- piperidyl)-3- pyridyl]-3- (oxetan-3-yloxy)- 1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E164
J1
496
497


 


A188




1-[3- (dimethylamino) phenyl]-3- isopropyl-4- (tetrahydropyran- 4- ylmethoxy)pyrazolo [3,4-b]pyridine- 6-carboxylic acid
HP07
J3
438
439


 


A189




1-(4- fluorophenyl)-3- isopropyl-4- (tetrahydropyran- 4- ylmethoxy)pyrazolo [3,4-b]pyridine- 6-carboxylic acid
HP11
J3
413
414


 


A190




1-(4- fluorophenyl)-3- isopropyl-4-(2- tetrahydropyran- 4- ylethoxy)pyrazolo [3,4-b]pyridine-6- carboxylic acid
HP11
J3
427
428


 


A191




3-cyclobutyl-4-[4- (1-methoxy-1- methyl-ethyl)-1- piperidyl]-1- phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E163
J8
448
449


 


A192




4-[3- (dimethylamino) p0ropoxy]-1-(4- fluorophenyl)-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
HP11
J3
400
401


 


A193




1-(4- fluorophenyl)-3- isopropyl-4-(3- morpholinopropoxy) pyrazolo[3,4- b]pyridine-6- carboxylic acid
HP11
J3
442
443


 


A194




1-(4- fluorophenyl)-3- isopropyl-4-[(3- methyloxetan-3- yl)methoxy]pyrazolo [3,4-b]pyridine-6- carboxylic acid
HP11
J3
399
400


 


A195




1-(4- fluorophenyl)-3- isopropyl-4- (tetrahydrofuran- 2- ylmethoxy)pyrazolo [3,4-b]pyridine- 6-carboxylic acid
HP11
J3
399
400


 


A196




3-cyclobutyl-4-[3- (dimethylamino) propoxy]-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
HP10
J3
394
395


 


A197




3-cyclobutyl-1- phenyl-4-[3-(1- piperidyl)propoxy] pyrazolo[3,4- b]pyridine-6- carboxylic acid
HP10
J3
434
435


 


A198




4-[(3,3-difluoro- 1-methyl- cyclobutyl)methoxy]- 1-(4- fluorophenyl)-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
HP11
J3
433
434


 


A199




1-(4- fluorophenyl)-3- isopropyl-4-[3-(1- piperidyl)propoxy] pyrazolo[3,4- b]pyridine-6- carboxylic acid
HP11
J3
440
441


 


A200




1-(4- fluorophenyl)-3- isopropyl-4-[2- methoxy-1- (methoxymethyl) ethoxy]pyrazolo[3,4- b]pyridine-6- carboxylic acid
HP11
J3
417
418


 


A201




1-(4- fluorophenyl)-4- [4-(1-hydroxy-1- methyl-ethyl)-1- piperidyl]-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E166
J1
440
441


 


A202




3-cyclobutyl-1-(4- fluorophenyl)-4- [4- (methoxymethyl)- 1- piperidyl]pyrazolo [3,4-b]pyridine- 6-carboxylic acid
E167
J1
438
439


 


A203




3-cyclobutyl-1-(4- fluorophenyl)-4- (tetrahydropyran- 4- ylmethoxy)pyrazolo [3,4-b]pyridine- 6-carboxylic acid
E171
J1
425
426


 


A204




3-cyclobutyl-4-[4- (1-hydroxy-1- methyl-thyl)-1- piperidinyl]-1- phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E170
J1
434
435


 


A205




4-[4- (dimethylamino)- 1-piperidyl]-1-(4- fluorophenyl)-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E174
J1
425
426


 


A206




1-(4- fluorophenyl)-3- isopropyl-4-[4-(1- methyl-4- piperidyl)-1- piperidyl]pyrazolo [3,4-b]pyridine- 6-carboxylic acid
E175
J1
479
480


 


A207




4-[(1-acetyl-4- piperidyl)methoxy]- 1-(4- fluorophenyl)-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E176
J1
454
455


 


A208




1-(4- fluorophenyl)-3- isopropyl-4-[(1- methoxycarbonyl- 4- piperidyl)methoxy] pyrazolo[3,4- b]pyridine-6- carboxylic acid
E178
J1
470
471


 


A209




3-cyclobutyl-4- (1,1-dioxo-1,4- thiazinan-4-yl)-1- phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E196
J1
426
427


 


A210




3-cyclobutyl-1- phenyl-4-(4- propoxy-1- piperidyl)pyrazolo [3,4-b]pyridine- 6-carboxylic acid
E078
J1
434
435


 


A211




3-cyclobutyl-4-(1- oxa-7- azaspiro[3.5]nonan- 7-yl)-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E085
J1
418
419


 


A212




3-isopropyl-4-(4- methoxy-1- piperidyl)-1-(2- morpholino-4- pyridyl)pyrazolo [3,4-b]pyridine-6- carboxylic acid
A257 Specific example
J7
480
481


 


A213




3-cyclobutyl-4-(1- methoxycarbonyl- 3,3a,4,6,7,7a- hexahydro-2H- pyrrolo[3,2- c]pyridin-5-yl)-1- phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E129
J1
476
477


 


A214




(1-acetyl- 3,3a,4,6,7,7a- hexahydro-2H- pyrrolo[3,2- c]pyridin-5-yl)-3- cyclobutyl-1- phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E132
J1
460
461


 


A215




3-isopropyl-4-(4- methoxy-1- piperdyl)-1-(6- morpholino-2- pyridyl)pyrazolo [3,4-b]pyridine-6- carboxylic acid
A259
J7
480
481


 


A216




3-cyclobutyl-4-[4- (fluoromethyl)-1- piperidyl]-1- phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
HP10
J4 Specific example
408
409


 


A217




4-(3- azaspiro[5.5]undecan- 3-yl)-3- cyclobuyl-1- phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
HP10
J4
444
445


 


A218




3-cyclobutyl-4-[4- (cyclopentoxy)-1- piperidyl]-1- phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E139
J1
460
461


 


A219




3-cyclobutyl-4-[4- (cyclohexyloxy)-1- piperidyl]-1- penyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E140
J1
474
475


 


A220




3-cyclobutyl-4-[4- (cyclopropylmethoxy)- 1-piperidyl]- 1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E141
J1
446
447


 


A221




4-(4- methoxyphenyl)- 3-methyl-1-(2- methylpropyl)- 1H-pyrazolo[3,4- b]pyridine-6- carboxylic acid
ALP06, 3524- 36-5
J2
339
340


 


A222




4-(4- morpolinophenyl)- 1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
127-17- 3, 1204- 86- 0,826- 85-7
Specific example
400
401


 


A223




1-isopropyl-4-(4- methoxyphenyl)- 3-methyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
ALP06, 1124- 16-9
J2
325
326


 


A224




1-cyclopropyl-3- methyl-4-(4- morpholinophenyl) pyrazolo[3,4- b]pyridine-6- carboxylic acid
ALP01, AMP15
J2
378
379


 


A225




4-[(1-acetyl-4- piperidyl)methoxy]- 3-cyclobutyl-1- phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
A261
J9 Specific example
448
449


 


A226




1-cyclohexyl-3- methyl-4-(4- morpholinophenyl) pyrazolo[3,4- b]pyridine-6- carboxylic acid
ALP01, 65647- 82-1
J2
420
421


 


A227




4-(4-cyano-1- piperidinyl)-1-(4- fluorophenyl)-3- isopropyl- pyrazolo[3, 4- b]pyridine-6- carboxylic acid
E142
J1
407
408


 


A228




3-isopropyl-4-[4- (methoxymethyl)- 1-piperidyl]-1-(1- methyl-6-oxo- pyridazin-3- yl)pyrazlo[3,4- b]pyridine-6- carboxylic acid
E157
J1
440
441


 


A229




1-(4- fluorophenyl)-3- isopropyl-4-[2- methoxyethyl (methyl)amino] pyrazolo[3,4-bpyridine- 6-carboxylic acid]
E165
J1
386
387


 


A230




1-(4- fluorophenyl)-3- isopropyl-4-[2-(1- methyl-2- piperidyl)ethoxy] pyrazolo[3,4- b]pyridine-6- carboxylic acid
HP11
J3
440
441


 


A231




4-[(1-acetyl-4- fluoro-4- piperidyl)methoxy]- 1-(4- fluorophenyl)-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
HP11, ALC03
J3
472
473


 


A232




1-(4- fluorophenyl)-3- isopropyl-4-[2- [isopropyl(oxetan- 3- yl)amino]ethoxy] pyrazolo[3,4- b]pyridine-6- carboxylic acid
HP11, ALC04
J3
456
457


 


A233




1-(4- fluorophenyl)-3- isopropyl-4-[(4- isopropylmorpholin- 3- yl)methoxy]pyrazolo [3,4- b]pyridine-6- carboxylic acid
HP11, ALC04 (rearrange- ment)
J3
456
457


 


A234




4-(1,4-dioxan-2- ylmethoxy)-1-(4- fluorophenyl)-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
HP11, ALC05 (rearrange- ment
J3
415
416


 


A235




1-(4- fluorophenyl)-3- isopropyl-4-[2- (oxetan-3- yloxy)ethoxy] pyrazolo[3,4- b]pyridine-6- carboxylic acid
HP11, ALC05
J3
415
416


 


A236




1-(2,6- dimethylpyridin- 4-yl)-4-[4- (methoxymethyl) piperidin-1-yl]-3- (propan-2-yl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E195
J1
437
438


 


A237




3-cyclobutyl-4- [(1- methoxycarbonyl- 4- piperidyl)methoxy]- 1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
A261
J0 Specific example
464
465


 


A238




4-(4- azidophenyl)-1- [3- (dimethylamino) phenyl]-3-(propan- 2-yl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E199
J1
441
442


 


A239




3-cyclobutyl-4-(4- isopropylpiperazin- 1-yl)-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E158
J1
419
420


 


A240




4-(4- cyclobutylpiperazin- 1-yl)-1-(4- fluorophenyl)-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E162
J1
437
438


 


A241




1-(4- fluorophenyl)-3- isopropyl-4-[4- (2,2,2- trifluoroethyl) piperazin-1- yl]pyrazolo[3,4- b]pyridine-6- carboxylic acid
E156
J1
465
466


 


A242




1-(3- bromophenyl)-3- isopropyl-4-(4- morpholinophenyl) pyrazolo[3,4- b]pyridin-6- carboxylic acid
ALP01, AMP05
J2
520- 522
521- 523


 


A243




3-tert-butyl-1- cyclopentyl-4-(6- morpholino-3- pyridyl)pyrazolo [3,4-b][yridine-6- carboxylic acid
ALP05, AMP37
J2
449
450


 


A244




4-(1-tert- butoxycarbonyl- 4-piperidyl)-1-(4- fluorophenyl)-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E197
J1
482
483


 


A245




3-isopropyl-4-(6- morpholino-3- pyridyl)-1- phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E007
J1
443
444


 


A246




4-(4- bromopenyl)-3- methyl-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
ALP19, 1131- 18-6
J2
407- 409
408- 410


 


A247




1-cyclohexyl-3- isopropyl-4-(6- morpholino-3- pyridyl)pyrazolo [3,4-b]pyridine-6- carboxylic acid
ALP05, AMP23
J2
449
450


 


A248




3-(azetidin-3-yl)- 1-cyclohexyl-4- [2- (dimethylamino) pyrimidin-5- yl]pyrazolo[3,4- b]pyridine-6- carboxylic acid
ALP03, AMP38
J2
421
422


 


A249




1-cyclohexyl-4- [2- (dimethylamino) pyrimidin-5-yl]-3- (1- methoxycarbonyl azetidin-3- yl)pyrazolo[3,4- b]pyridine-6- carboxylic acid
A248
J9 Specific example
479
480


 


A250




4-(6-chloro-3- pyridyl)-1- cyclohexyl-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
ALP07, AMP23
J2
398- 400
399- 401


 


A251




1-cyclohexyl-3- cyclopropyl-4-[6- (dimethylamino)- 3- pyridyl]pyrazolo [3,4-b]pyridine-6- carboxylic acid
E033
J1
405
406


 


A252




1-[3-(3- benzyloxyazetidin- 1-yl)phenyl]-3- isopropyl-4-(4- morpholinophenyl) pyrazolo[3,4- b]pyridine-6- carboxylic acid
A242
J7
603
604


 


A253




3-cyclobutyl-4-[4- [(1,1-dioxo-1,4- thiazinan-4- yl)methyl]-4- methoxy-1- piperidyl]-1- phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E150
J8
553
554


 


A254




3-isopropyl-4-(4- morpholinophenyl)- 1- tetrahydrofuran-3- yl-pyrazolo[3,4- b]pyridine-6- carboxylic acid
ALP01, AMP27
J2
436
437


 


A255




1-(3- fluorophenyl)-3- isopropyl-4-[6- [methyl(tetrahydro- pyran-4- yl)amino]-3- pyridyl]pyrazolo [3,4-b]pyridine-6- carboxylic acid
E137
J1
489
490


 


A256




4-(4- morpholinophenyl)- 3-oxo-1-phenyl- 2H-pyrazolo[3,4- b]pyridine-6- carboxylic acid
ALP01, 70373- 98-7
J2
416
417


 


A257




1-(2-bromo-4- pyridyl)-3- isopropyl-4-(4- methoxy-1- piperidyl)pyrazolo [3,4-b]pyridine- 6-carboxylic acid
E108
J1
473- 475
474- 476


 


A258




4-[6-(4-cyano-1- piperidyl)-3- pyridyl]-3-(3- fluorocycloutyl)- 1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E120
J1
496
497


 


A259




1-(6-bromo-2- pyridyl)-3- isopropyl-4-(4- methoxy-1- piperidyl)pyrazolo [3,4-b]pyridine- 6-carboxylic acid
E133
J1
473- 475
474- 476


 


A260




3-cyclobutyl-1- phenyl-4- (tetrahydrofuran- 2- ylmethoxy)pyrazolo [3,4-b]pyridine- 6-carboxylic acid
HP10
J3
393
394


 


A261




3-cyclobutyl-1- phenyl-4-(4- piperidylmethoxy) pyrazolo[3,4- b]pyridine-6- carboxylic acid
A262
I25
406
407


 


A262




4-[(1-tert- butoxycarbonyl- 4- piperidyl)methoxy]- 3-cyclobutyl-1- phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
HP10
J3
506
507


 


A263




4-[(1-tert- butoxycarbonyl- 4- piperidyl)methoxy]- 1-(4- fluorophenyl)-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
HP11
J3
512
513


 


A264




3-cyclobutyl-4-[2- (1-methyl-2- piperidyl)ethoxy]- 1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
HP10
J3
434
435


 


A265




3-cyclobutyl-4-[2- methoxy-1- (methoxymethyl) ethoxy]-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
HP10
J3
411
412


 


A266




3-cyclobutyl-4-[2- [isopropyl(oxetan- 3- yl)amino]ethoxy]- 1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
HP10
J3
450
451


 


A267




4-[4- (cyanomethyl)-4- hydroxy-1- piperidyl]-3- cyclobutyl-1- phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E179
J1
431
432


 


A268




3-cyclobutyl-4-(4- morpholino-1- piperidyl)-1- phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
HP10
J10 Specific example
461
462


 


A269




3-cyclobutyl-1- phenyl-4-[4- (2,2,2- trifluoroethyl) piperazin-1- yl]pyrazolo[3,4- b]pyridine-6- carboxylic acid
E180
J1
459
460


 


A270




3-cyclobutyl-4-[4- (2- morpholinoethyl)- 1-piperidyl]-1- phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
HP10
J10 Specific example
489
490


 


A271




4-[(3aR,7aS)-1- acetyl- 3,3a,4,6,7,7a- hexahydro-2H- pyrrolo[3,2- c]pyridin-5-yl]-3- cyclobutyl-1- phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
HP10
J10, I25, J9 Specific example
459
458 (ESI−)


 


A272




3-isopropyl-1-(2- morpholino-4- pyridyl)-4- (tetrahydropyran- 4- ylmethoxy)pyrazolo [3,4-b]pyridine- 6-carboxylic acid
E181
J6
481
482


 


A273




4-(4- ethoxycarbonyl- piperazin-1-yl)-1- (4-fluorophenyl)- 3-isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E184
J1
455
456


 


A274




1-(4- fluorophenyl)-3- isopropyl-4-(3- methyl-2-oxo-1- oxa-3,8- diazaspiro[4.5] decan-8- yl)pyrazolo[3,4- b]pyridine-6- carboxylic acid
E185
J1
467
468


 


A275




1-(4- fluorophenyl)-3- isopropyl-4-[3- (trifluoromethyl) piperazin-1- yl]pyrazolo[3,4- b]pyridine-6- carboxylic acid
E186
J1
451
452


 


A276




1-(4- fluorophenyl)-3- isopropyl-4-[4-(2- methoxyethyl) piperazin-1- yl]pyrazolo[3,4- b]pyridine-6- carboxylic acid
E187
J1
441
442


 


A277




4-(2,4-dioxo- 1,3,8- triazaspiro[4.5] decan-8-yl)-1-(4- fluorophenyl)-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E188
J1
466
467


 


A278




4-[4- (ethoxyethyl)-4- fluoro-1- piperidyl]-1-(4- fluorophenyl)-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E189
J1
458
459


 


A279




4-[4-fluoro-(2- methoxymethyl)- 1- piperidyl]-1-(4- fluorophenyl)-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E190
J1
488
489


 


A280




4-[(3R,4R)-3- fluoro-4-hydroxy- 1-piperidyl]-1-(4- fluorophenyl)-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E191
J1
416
417


 


A281




4-[4-fluoro-4- (methoxymethyl)- 1-piperidyl]-1-(4- fluorophenyl)-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E192
J1
444
445


 


A282




4-[3-fluoro-3-(2- methoxyethoxymethyl)- 1- piperidyl]-1-(4- fluorophenyl)-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E193
J1
488
489


 


A283




1-(4- fluorophenyl)-3- isopropyl-4-[4-(1- piperidyl)-1- piperidyl]pyrazolo [3,4-b]pyridine- 6-carboxylic acid
E194
J1
465
466


 


A284




3-cyclobutyl-4- [(3R)-3- (hydroxymethyl)- 1-piperidyl]-1- phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
HP10
J1
406
407


 


A285




3-cyclobutyl-1- phenyl-4-{4- [(pyrrolidin-1- yl)methyl]piperidin- 1-yl}-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E357
J10 Specific example
459
460


 


A286




3-cyclobutyl-1-(4- fluorophenyl)-4- {4-[2- (methoxymethyl) morpholin-4- yl]piperidin-1- yl}-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E354
J1, Specific example
523
523


 


A287




3-cyclobutyl-1-(4- fluorophenyl)-4- {4-[4-(propan-2- yl)piperazin-1- yl]piperidin-1- yl}-1H- pyrazolo3,4- b]pyridine-6- carboxylic acid
E355
J1
520
521


 


A288




3-cyclobutyl-1-(4- fluorophenyl)-4- (4-methoxy[1,4′- bipiperidin]-1′- yl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E356
J1
507
508


 


A289




3-cyclobutyl-4- (4,4-difluoro[1,4′- bipiperidin]-1′- yl)-1-(4- fluorophenyl)-1H- pyrazolo[34- b]pyridine-6- carboxylic acid
E358
J1
513
514


 


A290




4-[4-(2- cyanomorpholin- 4-yl)piperidin-1- yl]-3-cyclobutyl- 1-(4- fluorophenyl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E359
J1
504
505


 


A291




3-cyclobutyl-1-(4- fluorophenyl)-4- [4-(2-oxa-5- azabicyclo[2.2.1] heptan-5- yl)piperidin-1-yl]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylic acid
E360
J1
491
492


 


A292




3-cyclobutyl-1-(4- fluorophenyl)-4- {4-[methyl(oxan- 4- yl)amino]piperidin- 1-yl}-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E361
J1
507
508


 


A293




3-cyclobutyl-1-(4- fluorophenyl)-4- {4-[3- (trifluoromethyl) pyrrolidin-1- yl]piperidin-1- yl}-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E362
J1
531
532


 


A294




4-[4-(3- cyanopyrrolidin- 1-yl)piperidin-1- yl]-3-cyclobutyl- 1-(4- fluorophenyl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E363
J1
488
489


 


A295




4-(3-cyano[1,4′- bipiperidin]-1′- yl)-3-cyclobutyl- 1-(4- fluorophenyl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E364
J1
502
503


 


A296




3-cyclobutyl-4-(3- fluoro[1,4′- bipiperidin]-1′- yl)-1-(4- fluorophenyl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E365
J1
495
496


 


A297




3-cyclobutyl-1-(4- fluorophenyl)-4- [4-(3- methoxyazetidin- 1-yl)piperidin-1- yl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E366
J1A
479
480


 


A298




3-cyclobutyl-1-(4- fluorophenyl)-4- [3- (trifluoromethyl) [1,4′-bipiperidin]- 1′-yl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E367
J1A
545
546


 


A299




3-cyclobutyl-1-(4- fluorophenyl)-4- (3-methoxy[1,4′- bipiperidin]-1′- yl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E368
J1A
507
508


 


A300




3-cyclobutyl-4-[4- (2,2- dimethylmorpholin- 4-yl)piperidin- 1-yl]-1-(4- fluorophenyl)-1H- pyrazolo[3,4- b]pyridin-6- carboxylic acid
E369
J1A
507
508


 


A301




3-cyclobutyl-4- {4-[4- (ethoxycarbonyl) piperazin-1- yl]piperidin-1- yl}-1-(4- fluorophenyl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E370
J1A
550
551


 


A302




3-cyclobutyl-1-(4- fluorophenyl)-4- [1-(propan-2- yl)octahydro-5H- pyrrolo[3,2- c]pyridin-5-yl]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylic acid
E371
J1
477
478


 


A303




3-cyclobutyl-4-(1- cyclobutyloctahydro- 5H- pyrrolo[3,2- c]pyridin-5-yl)-1- (4-fluorophenyl)- 1H-pyrazolo[3,4- b]pyridine-6- carboxylic acid
E372
J1
489
490


 


A304




3-cyclobutyl-1-(4- fluorophenyl)-4- [1-(oxetan-3- yl)octahydro-5H- pyrrolo[3,2- c]pyridin-5-yl]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylic acid
E373
J1
491
492


 


A305




3-cyclobutyl-1-(4- fluorophenyl)-4- [1-(oxan-4- yl)octahydro-5H- pyrrolo[3,2- c]pyridin-5-yl]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylic acid
E374
J1
519
520


 


A306




3-cyclobutyl-4-(4- fluoro-[1,4′- bipiperidin]-1′- yl)-1-(4- fluorophenyl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E375
J1
495
496


 


A307




3-cyclobutyl-1-(4- fluorophenyl)-4- {4-[(2- methoxyethyl) (methyl)amino]piperidin- 1-yl}-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E376
J1A
481
482


 


A308




3-cyclobutyl-1-(4- fluorophenyl)-4- [4-(morpholin-4- yl)piperidin-1-yl]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylic acid
E377
J1
479
480


 


A309




4-([1,4′- bipiperidin]-1′- yl)-3-cyclobutyl- 1-(4- fluorophenyl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E378
J1
477
478


 


A310




3-cyclobutyl-1-(4- fluorophenyl)-4- [3-(morpholin-4- yl)-1-oxa-8- azaspiro[4.5]decan- 8-yl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E381
J1
535
536


 


A311




3-cyclobutyl-1-(4- fluorophenyl)-4- {4-[2-(morpholin- 4- yl)ethyl]piperidin- 1-yl}-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E382
J1
507
508


 


A312




3-cyclobutyl-4- {4-[2-(4- methylpiperidin- 1- yl)ethyl]piperidin- 1-yl}-1-phenyl- 1H-pyrazolo[3,4- b]pyridine-6- carboxylic acid
E383
J1
501
502


 


A313




3-cyclobutyl-4-[4- (4- cyclopropylpiperazin- 1- yl)piperidin-1-yl]- 1-phenyl-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E384
J1
500
501


 


A314




3-cyclobutyl-1- phenyl-4-[4- (propan-2- yl)piperiazin-1- yl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E385
J1
419
420


 


A315




3-cyclobutyl-4-[4- (methoxymethyl) piperidin-1-yl]-1- (2- methoxypyridin- 4-yl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E388
J1
451
452


 


A316




3-cyclobutyl-4-[4- (methoxymethyl) piperidin-1-yl]-1- [2-(oxan-4- yl)pyridin-4-yl[- 1H-pyrazolo]3,4- b]pyridine-6- carboxylic acid
E391
J1A
505
506


 


A317




3-cyclobutyl-1-(2- methoxypyridin- 4-yl)-4-[4- (morpholin-4- yl)piperidin-1-yl]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylic acid
E394
J1A
492
493


 


A318a




3-cyclobutyl-1-(3- methylphenyl)-4- [4-(morpholin-4- yl)piperidin-1-yl]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylic acid
E395
J1A Specific example
475
476


 


A318b




3-cyclobutyl-1-(3- methoxyphenyl)- 4-[4-(morpholin- 4-yl)piperidin-1- yl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E396
J1A
491
492


 


A319




3-cyclobutyl-4-[4- (morpholin-4- yl)piepridin-1-yl]- 1-[4- (trifluoromethyl) phenyl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E397
J1A
529
530


 


A320




3-cyclobutyl-1-(4- fluoro-3- methylphenyl)-4- [4-(morpholin-4- yl)piperidin-1-yl]- 1H-pyrazolo[3,4- b]pyridin-6- carboxylic acid
E398
J1A
493
494


 


A321




3-cyclobutyl-4-[4- (morpholin-4- yl)piperidin-1-yl]- 1-[3- (trifluoromethyl) phenyl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E399
J1A
529
530


 


A322




3-cyclobutyl-4-[4- (morpholin-4- yl)piperidin-1-yl]- 1-{2-[(propan-2- yl)oxy]pyridin-4- yl}-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E400
J1A
520
521


 


A323




1-[2- (benzyloxy) pyridin-4-yl]-3- cyclobutyl-4-[4- (morpholin-4- yl)piperidin-1-yl]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylic acid
E401
J1A
568
569


 


A324




3-cyclobutyl-1-(2- hydroxypyridin-4- yl)-4-[4- (morpholin-4- yl)piperidin-1-yl]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylic acid
E402
J1A
478
479


 


A325




3-cyclobutyl-1-[2- (difluoromethoxy) pyridin-4-yl]-4- [4-(morpholin-4- yl)piperidin-1-yl]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylic acid
E403
J1A
528
529


 


A326




3-cyclobutyl-1-(3- fluorophenyl)-4- [4-(morpholin-4- yl)piperidin-1-yl]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylic acid
E404
J1A
479
480


 


A327




3-cyclobutyl-1- (2,2-difluoro-2H- 1,3-benzodioxol- 5-yl)-4-[4- (morpholin-4- yl)piperidin-1-yl]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylic acid
E405
J1A
541
542


 


A328




3-cyclobutyl-4-[4- (morpholin-4- yl)piperidin-1-yl]- 1-[2-(oxan-4- yl)pyridin-4-yl]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylic acid
E407
J1A
546
547


 


A329




3-cyclobutyl-4-[1- (4,4- difluorocyclohexyl) piperidin-4-yl]- 1-(4- fluorophenyl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E414
J1A
512
513


 


A330




3-cyclobutyl-1-(4- fluorophenyl)-4- [1-(propan-2- yl)piperidin-4-yl]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylic acid
E415
J1A
436
437


 


A331




3-cyclobutyl-1-(4- fluorophenyl)-4- [1-(oxan-4- yl)piperidin-4-yl]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylic acid
E416
J1A
478
479


 


A332




3-cyclobutyl-1-(4- fluorophenyl)-4- {1-[(oxan-4- yl)methyl]piperidin- 4-yl}-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E417
J1A
492
493


 


A333




3-cyclobutyl-4- {1-[(2,5- dimethoxyoxolan- 3- yl)methyl]piperidin- 4-yl}-1-(4- fluorophenyl)-1H- pyrazolo[3,4- b]pyridin-6- carboxylic acid
E418
J1A
538
439


 


A334




3-cyclobutyl-1-(4- fluorophenyl)-4- [1-(3,3,3- trifluoropropyl) piperidin-4-yl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E419
J1A
490
491


 


A336




3-cyclobutyl-4-[1- (cyclopropylmethyl) piperidin-4-yl]- 1-(4- fluorophenyl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E421
J1A
448
449


 


A337




3-cyclobutyl-4- {4-[2-(4- methylpiperidin- 1- yl)ethyl]piperidin- 1-yl}-1-phenyl- 1H-pyrazolo[3,4- b]pyridine-6- carboxylic acid
E412
J1A
501
502


 


A338




3-cyclobutyl-4-[4- (ethoxymethyl)-4- fluoropiperidin-1- yl]-1-phenyl-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E408
J1
452
453


 


A339




3-cyclobutyl-4- {4-fluoro-4-[(2- methoxyethoxy) methyl]piperidin-1- yl}-1-phenyl-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E409
J1
482
483


 


A340




3-cyclobutyl-4- {3-fluoro-3-[(2- methoxyethoxy) methyl]piperidin-1- yl}-1-phenyl-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E410
J1
482
483


 


A341




3-cyclobutyl-4-[4- fluoro-4- (methoxymethyl) piperidin-1-yl]-1- phenyl-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E411
J1
438
439


 


A342




3-cyclobutyl-4-[4- (morpholin-4- yl)piperidin-1-yl]- 1-{2-[(propan-2- yl)oxy]pyrimidin- 4-yl}-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E422
J11
521
522


 


A343




3-cyclobutyl-1-(2- ethoxypyrimidin- 4-yl)-4-[4- (morpholin-4- yl)piepridin-1-yl]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylic acid
E422
J11 Specific example
507
508


 


A344




3-cyclobutyl-1-(4- fluorophenyl)-4- (4-methoxy[1,4′- bipiperidin]-1′- yl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E424
J1A
507
508


 


A345




3-cyclobutyl-4-[4- (morpholin-4- yl)cyclohexyl]-1- phenyl-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E433
J1A
460
461


 


A346




3-cyclobutyl-1-(4- fluorophenyl)-4- {4-[4-(propan-2- yl)piperazin-1- yl]piperidin-1- yl}-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E434
J1
520
521


 


A347




1-cyclohexyl-3- [(propan-2- yl)oxy]-4-(4-{[4- (propan-2- yl)piperazin-1- yl]methyl}phenyl)- 1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E435
J1
519
520


 


A348




1-cyclohexyl-4- {4-[(4- methoxypiperidin- 1- yl)methyl]phenyl}- 3-[(propan-2- yl)oxy]-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E436
J1
506
507


 


A349




1-cyclohexyl-4- {4-[(5- methylhexahydro pyrrolo[3,4- b]pyrrol-2(1H)- yl)methyl]phenyl}- 3-[(propan-2- yl)oxy]-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E437
J1
517
518


 


A350




1-cyclohexyl-4- (4-formylphenyl)- 3-[(propan-2- yl)oxy]-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E425
J1
407
408


 


A351




4-{4-[5-(tert- butoxycarbonyl) hexahydropyrrolo [3,4-c]pyrrole- 2(1H)- carbonyl]phenyl}- 1-cyclohexyl-3- [(propan-2- yl)oxy]-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E439
J1A
617
618


 


A352




1-cyclohexyl-4- [4-(5- methylhexahydro pyrrolo[3,4- c]pyrrole-2(1H)- carbonyl)phenyl]- 3-[(propan-2- yl)oxy]-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
R440
J1A
531
532


 


A353




1-cyclohexyl-4- {4-[3- (dimethylamino) azetidine-1- carbonyl]phenyl}- 3-[(propan-2- yl)oxy]-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E441
J1A
505
506


 


A354




1-cyclohexyl-4- {4-[(8-methyl-2- oxa-5,8- diazaspiro[3.5] nonan-5- yl)methyl]phenyl}- 3-[(propan-2- yl)oxy]-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E444
J1A
533
534


 


A355




4-[4-(4-cyano-1- methylpiperidin- 4-yl)phenyl]-1- cyclohexyl-3- [(propan-2- yl)oxy]-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E445
J1A
501
502


 


A356




3-cyclobutyl-1-(4- fluorophenyl)-4- [4-(3- fluoropyrrolidin- 1-yl)piperidin-1- yl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E427
J1
481
482


 


A357




4-[4-(3- cyanoazetidin-1- yl)piperidin-1-yl]- 3-cyclobutyl-1-(4- fluorophenyl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E428
J1
474
475


 


A358




3-cyclobutyl-1-(4- fluorophenyl-4- [4-(3- methoxypyrrolidin- 1-yl)piperidin- 1-yl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E429
J1
493
494


 


A360




3-cyclobutyl-1-(4- fluorophen yl)-4- {4-[1-(morpholin- 4- yl)ethyl]piperidin- 1-yl}-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E460
J1
507
508


 


A361




3-cyclobutyl-4- fluorophenyl)-4- {[4-(morpholin-4- yl)piperidin-1- yl]methyl}-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
HP19
J13 Specific example
493
494


 


A362




3-cyclobutyl-1-(4- fluorophenyl)-4- (4-hydroxy[1,4′- bipiperidin]-1′- yl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E492
J1
493
494


 


A363




4-([1,4′- bipiperidin]-1′- yl)-3-cyclobutyl- 1-(4- fluorophenyl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E493
J1
493
494


 


A364




3-cyclobutyl-1- cyclohexyl-4-{4- [(morpholin-4- yl)methyl]phenyl}- 1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
HP25, 364794- 79-6
J14
474
475


 


A365




3-cyclobutyl-1- cyclohexyl-4-{4- [2-(morpholin-4- yl)ethyl]phenyl}- 1H-pyrazolo[3,4- b]pyridine-6- carboxylic acid
HP25, 1150114 -55-8
J14
488
489


 


A366




3-cyclobutyl-1- cyclohexyl-4-[4- (2-methylpyridin- 4-yl)piperazin-1- yl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E461
J1
474
475


 


A367




3-cyclobutyl-1- cyclohexyl-4-{4- [1-(morpholin-4- yl)ethyl]phenyl}- 1H-pyrazolo[3,4- b]pyridine-6- carboxylic acid
HP25, 1206594 -12-8
J14
488
489


 


A368




3-cyclobutyl-1- cyclohexyl-4-{4- [4-(propan-2- yl)piperazin-1- yl]phenyl}-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
HP25, 1073354 -18-3
J14
501
502


 


A369




3-cyclobutyl-1- cyclohexyl-4-[6- (4- methylpiperazin- 1-yl)pyridin-3- yl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
A407, 109-01 3
J12
474
475


 


A370




3-cyclobutyl-1- cyclohexyl-4-{6- [4-(2- methoxyethyl) piperazin-1-0 yl]pyridin-3-yl}- 1H-pyrazolo[3,4- b]pyridine-6- carboxylic acid
A407, 13484- 40-7
J12
518
519


 


A371




3-cyclobutyl-1- cyclohexyl-4-{4- [4-(propan-2- yl)piperazin-1- yl]piperidin-1- yl}-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E462
J1
508
509


 


A372




4-[(3S)-4-benzyl- 3- methylpiperazin- 1-yl]-3- cyclobutyl-1- cyclohexyl-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E463
J1
487
488


 


A373




4-[(3R)-4-benzyl- 3- methylpiperazin- 1-yl]-3- cyclobutyl-1- cyclohexyl-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E464
J1
487
488


 


A374




3-cyclobutyl-4-[4- (4- cyclopropylpiperazin- 1- yl)piperidin-1-yl]- 1-(4- fluorophenyl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E465
J1
518
519


 


A375




3-cyclobutyl-4-(9- cyclopropyl-3,9- diazaspiro[5.5]undecan- 3-yl)-1-(4- fluorophenyl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E466
J1
503
504


 


A376




3-cyclobutyl-1-(4- fluorophenyl)-4- {4-[(pyrrolidin-1- yl)methyl]piperidin- 1-yl}-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E467
J1
477
478


 


A377




3-cyclobutyl-1-(4- fluorophenyl)-4- {4-[4-(2- methoxyethyl) piperazin-1- yl]piperidin-1- yl}-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E468
J1
536
537


 


A378




3-cyclobutyl-1-(4- fluorophenyl)-4- [9-(oxetan-3-yl)- 3,9- diazaspiro[5.5]undecan- 3-yl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E469
J1
519
520


 


A379




3-cyclobutyl-1-(4- fluorophenyl)-4- {4-[4-(ocetan-3- yl)piperazin-1- yl]piperidin-1- yl}_1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E470
J1
534
535


 


A380




1-cyclohexyl-4- {4-[(morpholin-4- yl)methyl]phenyl}- 3-[(propan-2- yl)oxy]-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E473
J1
479
479


 


A381




1-cyclohexyl-4- [4-(4- methylpiperazine- 1- carbonyl)phenyl]- 3-[(propan-2- yl)oxy]-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E474
J1
506
506


 


A382




3-cyclobutyl-1- cyclohexyl-4-[4- (pyridin-4- yl)piperazin-1- yl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E475
J1
461
461


 


A383




3- (cyclobutyloxy)- 1-cyclohexyl-4- {4-[(morpholin-4- yl)methyl]phenyl}- 1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E476
J11
491
491


 


A384




1-cyclohexyl-4- {4-[4- (dimethylamino) piperidine-1- carbonyl]phenyl}- 3-[(propan-2- yl)oxy]-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E477
J1
534
535


 


A385




1-cyclohexyl-4- {4-[(piperidin-1- yl)methyl]phenyl}- 3-[(propan-2- yl)oxy]-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E478
J1
477
477


 


A386




1-cyclohexyl-4- {4-[(4- methylpiperazin- 1- yl)methyl]phenyl}- 3-[(propan-2- yl)oxy]-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E479
J1
492
492


 


A387




1-cyclohexyl-3- [(propan-2- yl)oxy]-4-{4- [(pyrrolidin-1- yl)methyl]phenyl}- 1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E480
J1
463
463


 


A388




3-cyclobutyl-1-(4- fluorophenyl)-4- {[4- (methoxymethyl) piperidin-1- yl]methyl}-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E481
J1
453
453


 


A389




3-cyclobutyl-1-(4- fluorophenyl)-4- [(morpholin-4- yl)methyl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E471
J1
410
411


 


A390




3-cyclobutyl-1-(4- fluorophenyl)-4- [(4- methylpiperazin- 1-yl)methyl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E472
J1
423
424


 


A391




4-(4-cyano[1,4′- bipiperidin]-1′- yl)-3-cyclobutyl- 1-(4- fluorophenyl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E485
J1
502
503


 


A392




1-cyclohexyl-4- {4-[(4- cyclopropylpiperazin- 1- yl)methyl]phenyl}- 3-[(propan-2- yl)oxy]-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E482
J1
518
518


 


A393




1-cyclohexyl-4- [4-(4- cyclopropylpiperazin- 1-yl)phenyl]- 3-[(propan-2- yl)oxy]-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E484
J1
503
504


 


A394




3-cyclobutyl-4- [(1- cyclopropylpiperidin- 4- yl)methoxy]-1-(4- fluorophenyl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
HP26 ALC09
J3
464
465


 


A395




1-c7yclohexyl-3- [(propan-2- yl)oxy]-4-{4-[4- (propan-2- yl)piperazin-1- yl]phenyl}-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E483
J1
505
506


 


A396




3-cyclobutyl-1-(4- fluorophenyl)-4- {[1-(oxan-4- yl)piperidin-4- yl]methoxy}-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
HP26 ALC08
J3
508
509


 


A397




3-cyclobutyl-4- [(1- cyclohexylpiperidin- 4-yl)methoxy]- 1-(4- fluorophenyl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
HP26 ALC07
J3
506
507


 


A398




3-cyclobutyl-4- [(1- cyclobutylpiperidin- 4-yl)methoxy]- 1-(4- fluorophenyl)-1H- pyrazolo[3,4- b]pyri9dine-6- carboxylic acid
HP26 ALC06
J3
478
479


 


A399




3-cyclobutyl-1-(4- fluorophenyl)-4- {4-[4- (methoxycarbonyl) piperazin-1- yl]piperidin-1- yl}-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E486
J1
536
537


 


A400




4-[4-(4- acetypiperazin-1- yl)piperidin-1-yl]- 3-cyclobutyl-1-(4- fluorophenyl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E487
J1
520
521


 


A401




3-cyclobutyl-1- cyclohexyl-4-{4- [(morpholin-4- yl)m ethyl]piperidin- 1-yl}-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E488
J1
481
482


 


A402




3-cyclobutyl-1- cyclohexyl-4-{4- [2-(morpholin-4- yl)ethyl]piperidin- 1-yl}-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E489
J1
495
496


 


A403




3-cyclobutyl-1- cyclohexyl-4-[4- (morpholin-4- yl)piperidin-1-yl]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylic acid
E490
J1
467
468


 


A404




3-cyclobutyl-1-(4- fluorophenyl)-4- {4-[(morpholin-4- yl)methyl]piperidin- 1-yl}-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E491
J1
493
494


 


A405




3-cyclobutyl-1- cyclohexyl-4-[6- (4- cyclopropylpiperazin- 1-yl)pyridin- 3-yl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
A407, 20327- 23-5
J12 Specific example
500
501


 


A406




3-cyclobutyl-1- cyclohexyl-4-{6- [4-(propan-2- yl)piperazin-1- yl]pyridin-3-yl}- 1H-pyrazolo[3,4- b]pyridine-6- carboxylic acid
A407, 4318- 42-7
J12
502
503


 


A407




3-cyclobutyl-1- cyclohexyl-4-(6- fluoropyridin-3- yl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
HP25, 351019- 18-6
J14
394
395


 


A408




1-(4- fluorophenyl)-4- [4-(morpholin-4- yl)piperidin-1-yl]- 3-(propan-2-yl)- 1H-pyrazolo[3,4- b]pyridine-6- carboxylic acid
HP11, 442563- 55-5
J10 Specific example
467
468


 


A409




3-cyclobutyl-4-[4- (morpholin-4- yl)piperidin-1-yl]- 1-phenyl-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
HP10
J10
461
462


 


A410




3-cyclobutyl-1-[3- (difluoromethoxy) phenyl]-4-[4- (morpholin-4- yl)piperidin-1-yl]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylic acid
E510
J1
527
528


 


A411




1-cyclohexyl-4- (4-{[3- (dimethylamino) azetidin-1- yl]methyl}phenyl)- 3-[(propan-2- yl)oxy]-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
R426
J1A
491
492


 


A412




1-(4- fluorophenyl)-4- (4-methoxy[1,4′- bipiperidin]-1′- yl)-3-[(propan-2- yl)oxy]-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E511
J1A
511
512


 


A413




3-cyclobutyl-4-[4- (hydroxymethyl) piperidin-1-yl]-1- phenyl-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
HP10
J10, Specific example
406
407


 


A414




3-cyclobutyl-1- (4-fluorophenyl)- 4-(9-methyl-3,9- diazaspiro[5.5] undecan-3-yl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E515
J1
477
478


 


A415




3-cyclobutyl-4- [4- (ethoxycarbonyl) piperazin-1-yl]-1- (4-fluorophenyl)- 1H-pyrazolo[3,4- b]pyridine-6- carboxylic acid
E516
J1
467
468


 


A416




3-cyclobutyl-1- (4-fluorophenyl)- 4-{4-[(2- methylpropoxy) carbonyl]piperazin- 1-yl}-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
E517
J1
495
496









Method X1: Synthesis of Sulfonamide




A procedure similar to that described in J. Org. Chem. (1968) 33(2), 897 is followed: A round bottomed flask is charged with the sulfonyl chloride and diethyl ether (0.06 M), sealed with a septum and cooled in an ice bath. To the cooled solution is slowly added two molar equivalents of a dioxane solution of ammonia (0.5 M), and then the cold bath is removed. After 16 hours, the resulting heterogeneous mixture is filtered through filter paper. Volatiles are removed from the filtrate via rotary evaporation to give the sulfonamide which is used without further purification.
Illustrative Synthesis of S2: methyl 3-sulfamoylpropanoate




A dioxane solution of ammonia (0.5 M, 10.5 mL, 5.25 mmol, 2.05 equiv) was added at 0° C. to a solution of methyl 3-(chlorosulfonyl)propanoate (CAS: 15441-07-3, 0.476 g, 2.55 mmol) in diethyl ether (10 mL). The reaction mixture was stirred at 0° C. for 1 hour and then 16 hours at RT. The reaction mixture was filtered, and the filtrate was concentrated to give the titled compound which was used without further purification.
Method X2: Synthesis of Sulfonamide
Synthesis of 3-morpholinopropane-1-sulfonamide S10




Step 1: 3-(morpholin-4-yl)propane-1-sulfonyl chloride
3-Morpholinopropanesulfonic acid (CAS: 1132-61-2, 0.63 g, 3.0 mmol) was added to thionyl chloride (4.0 mL, 54.8 mmol, 18 equiv). Dimethylformamide (0.1 mL, 1.2 mmol, 0.4 equiv) was added, and the reaction mixture was stirred at RT for 5 hours. The reaction mixture was diluted with dichloromethane (4 mL) and dropped into heptane. Precipitation occurred, and the supernatant was removed. The residue dissolved in dichloromethane was dropped into pentane. The supernatant was removed, and the solid dried to give 3-morpholinopropanesulfonyl chloride hydrochloride.
Step 2: N,N-bis[(2,4-dimethoxyphenyl)methyl]-3-(morpholin-4-yl)propane-1-sulfonamide
Bis(2,4-dimethoxybenzyl)amine (CAS: 20781-23-1, 0.32 g, 1.0 mmol, 1.0 equiv) and potassium carbonate (0.28 g, 2.0 mmol, 2.0 equiv) were added to a solution of 3-morpholinopropanesulfonyl chloride hydrochloride (0.26 g, 1.0 mmol) in acetonitrile (20 mL). The reaction mixture was stirred at RT for 8 hours. The reaction mixture was concentrated and the residue partitioned between water and ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with heptane/ethyl acetate (100/0 to 0/100) to give N,N-bis[(2,4-dimethoxyphenyl)methyl]-3-morpholino-propane-1-sulfonamide.
Step 3: 3-(morpholin-4-yl)propane-1-sulfonamide
Trifluoroacetic acid (0.8 mL, 10.4 mmol, 39 equiv) was added to a solution of N,N-bis[(2,4-dimethoxyphenyl)methyl]-3-morpholino-propane-1-sulfonamide (0.135 g, 0.27 mmol) in dichloromethane (4 mL). The reaction mixture was stirred at RT for 16 hours and was added to a saturated aqueous solution of sodium hydrogencarbonate. The mixture was extracted with ethyl acetate and then with a 9:1 mixture of dichloromethane/isopropanol. The organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure to give the titled compound.
As an alternative preparation of S10, 3-chloropropane-1-sulfonamide (3.15 g, 20.0 mmol), morpholine (1.84, 21.0 mmol), sodium carbonate (4.24 g, 40.0 mmol) and sodium iodide (300 mg, 2.0 mmol) were heated in anhydrous dioxane (70 mL) at 70° C. for a day. The suspension was permitted to cool towards room temperature and then filtered through diatomaceous earth with an MTBE rinse. The filtrate was concentrated and chromatographed on silica (0 to 4% concentrated aqueous NH4OH/CH3CN) to give the titled compound (1.47 g). 1H NMR (400 MHz, CDCl3) δ ppm 5.41 (s, 2H), 3.70 (t, J=4.7 Hz, 4H), 3.23 (t, J=7.2 Hz, 2H), 2.54-2.43 (m, 6H), 2.10-2.02 (m, 2H); MS (DCI) m/z 209 (M+H)+.
Method X3. Synthesis of Sulfonamide
Synthesis of (2S)-2-(4-methylpiperazine-1-carbonyl)pyrrolidine-1-sulfonamide S11




The titled compound may be prepared by the method described in Ebden, et al. PCT Int. Appl. WO2004 011443, example 25, substituting N-methylpiperidine hydrochloride for dimethylamine hydrochloride. To 1-(tert-butoxycarbonyl)-L-proline (5.0 g) in DCM (50 mL) at 5° C. was added dicyclohexylcarbodiimide (5.22 g) and N-hydroxysuccinimide (2.91 g). The mixture was stirred at this temperature for 16 hours. The solid was filtered, and the filtrate cooled to 5° C. To this mixture was added triethylamine (9.80 mL) and N-methylpiperidine hydrochloride (4.7 g). The mixture was stirred at room temperature for 2 days, H2O (50 mL) was added, and the phases were separated. The organic fraction was washed with saturated sodium carbonate (2×20 mL) and brine (20 mL). This was then dried (MgSO4) and concentrated to dryness to afford tert-butyl (2S)-2-(4-methylpiperazine-1-carbonyl)pyrrolidine-1-carboxylate. This was then treated with 4 M aqueous HCl (20 mL), stirred at room temperature 3 hours, and concentrated in vacuo to dryness. A solution of the residue in dioxane was then treated with 2 grams of triethylamine and 10 grams of sulfamide, and the mixture was heated at reflux for 3 days before cooling. Solids were removed by filtration and washed with methanol. The combined filtrate and washing are concentrated in vacuo, and the residue was purified by column chromatography to give the titled compound.
Method X4. Synthesis of Sulfonamide
Synthesis of 4-(4-methylpiperazine-1-carbonyl)piperidine-1-sulfonamide S12




A solution of (4-methylpiperazin-1-yl)(piperidin-4-yl)methanone hydrochloride in dioxane was treated with 5 equivalents of triethylamine and 10 equivalents of sulfamide and heated at reflux for 3 days. The mixture was then cooled and filtered, and the solids were washed with methanol. The filtrate and washings were concentration in vacuo, and the residue was purified by column chromatography to give the titled compound.
Method X4B. Synthesis of Sulfamides




A solution of amine hydrochloride (from 1 to 2 equiv.) in dioxane is treated with triethylamine (from 1.1 to 2.2 equiv), and sulfamide (from 1 to 2 equiv) and refluxed until full conversion is observed. The mixture is then cooled to RT, and the residue is purified by flash column chromatography to give the desired sulfamide derivative.
Illustrative Synthesis of Compound S14




A solution of 3-methoxypyrrolidine hydrochloride ([136725-50-3], 136 mg, 0.98 mmol) in dioxane (2 mL) was treated with triethylamine (0.2 mL, 1.4 mmol) and sulfamide (7803-58-9, 130 mg, 1.3 mmol), and the mixture was refluxed for 16 hours. The mixture was then cooled to RT, and the residue was purified by column chromatography eluted with DCM/MeOH (9/1) to give the titled compound.
Method X5. Synthesis of Sulfamides




Step 1: benzyl (chlorosulfonyl)carbamate
A solution of chlorosulfonylisocyanate ([1189-71-5], 1 eq) in anhydrous DCM (2.5 vol.) is cooled down in an ice batch under argon atmosphere. Benzyl alcohol ([100-51-6], 1 eq) is added dropwise over a 15 minutes period. The reaction mixture is stirred for 5 minutes and allowed to warm up to RT. The reaction mixture is worked up when no more starting material remained, by adding n-pentane. The precipitate is filtered, washed with n-pentane, and dried at 40° C. under reduced pressure to give the titled compound.
Step 2: N-Benzyloxycarbonyl Protected Sulfamide
A solution of amine (1 eq) and N,N-diisopropylethylamine (1.2 eq) in anhydrous DCM (10 vol.) is cooled down in an ice bath under an argon atmosphere. The compound from Step 1 (1.2 eq) is added, and after 5 minutes, the solution is allowed to warm up to RT. The reaction mixture is worked up when no more starting material remained, by adding water. The organic phase is diluted, separated, and washed successively with an aqueous 1 M HCl solution and a saturated aqueous solution of NaCl. The organic phase is dried over magnesium sulfate, filtered and concentrated in vacuo. The crude sample is either purified by flash column chromatography or suspended in a mixture of n-heptane/ethyl acetate (9/1), refluxed for 15 minutes, and then left cooling down to RT. The precipitate is collected by filtration, washed with a mixture of n-heptane/ethyl acetate (9/1), and dried at 40° C. under reduced pressure to give the desired N-benzyloxycarbonyl protected sulfamide.
Step 3: N-Deprotected Sulfamide
A solution of N-benzyloxycarbonyl protected sulfamide (1 eq) in THF or MeOH (20 vol.) is degassed with nitrogen. 20% Pd(OH)2 w/w is added, and the reaction mixture is purged with H2. The mixture is stirred at room temperature under a hydrogen atmosphere (balloon) until no more starting material is observed. Additional 20% Pd(OH)2 is added if necessary. The reaction mixture is filtered over a diatomaceous earth pad that is washed with THF or MeOH. The filtrate is concentrated in vacuo. The residue is purified by preparative HPLC or by flash column chromatography or used as such in the next step.
Illustrative Synthesis of Intermediate S15: 4-(methoxymethyl)piperidine-1-sulfonamide




Step 1: benzyl (chlorosulfonyl)carbamate
A solution of chlorosulfonylisocyanate ([1189-71-5], 8.1 g, 57.4 mmol) in anhydrous DCM (20 mL) was cooled down in an ice bath under an argon atmosphere. Benzyl alcohol ([100-51-6], 5.9 mL, 57.4 mmol) was added dropwise over a 15 minutes period. The reaction mixture was stirred for 5 minutes and allowed to warm up to RT. After 10 minutes, n-pentane (20 mL) was added, and the resulting mixture was stirred at RT for 30 minutes. The precipitate was collected by filtration, washed with n-pentane, and dried at 40° C. under reduced pressure to give the titled compound.
Step 2. benzyl [4-(methoxymethyl)piperidine-1-sulfonyl]carbamate
A solution of 4-(methoxymethyl)piperidine hydrochloride ([399580-55-3], 1.0 g, 6.0 mmol) and N,N-diisopropylethylamine (2.3 mL, 13.3 mmol) in anhydrous DCM (10 mL) was cooled down in an ice bath under an argon atmosphere. Benzyl (chlorosulfonyl)carbamate from Step 1 (1.8 g, 7.2 mmol) was added and after 5 minutes, and the solution was allowed to warm up to RT. After 3 hours, water (10 mL) and DCM (10 mL) were added, and stirring was continued for 15 minutes. The organic phase was separated, washed successively with an aqueous 1 M HCl solution (2×10 mL), and a saturated aqueous solution of NaCl (10 mL). The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of DCM/MeOH to give the titled compound.
Step 3. 4-(methoxymethyl)piperidine-1-sulfonamide
A solution of compound from Step 2 (570 mg, 1.8 mmol) in THF (11 mL) was degassed with nitrogen. 20% Pd(OH)2 (w/w, 114 mg) was added, and the reaction mixture was purged with H2. The mixture was stirred for 20 hours at RT under a hydrogen atmosphere (balloon). The reaction mixture was filtered over a diatomaceous earth pad that was washed with THF. The filtrate was concentrated in vacuo to give the titled compound.







TABLE XIV







List of sulfonamides













Int.
Structure
Name
SM
method
MW
Mes





S1 




2- morpholinoethane- sulfonamide
103654- 84-8
X1
194



 


S2 




methyl 3- sulfamoylpropanoate
15441- 07-3
X1 Specific example
167



 


S3 




cyanomethane- sulfonamide
27869- 04-1
X1
120



 


S4 




tetrahydrofuran-3- sulfonamide
1207346- 29-9
X1
151



 


S5 




benzyl N-(2- sulfamoylethyl) carbamate
52530- 50-4
X1
258
259


 


S6 




methyl 2- sulfamoylacetate
52530- 50-4
X1
153



 


S7 




benzyl 3- sulfamoylpyrrolidine- 1-carboxylate
1035173- 74-0
X1
284



 


S8 




tetrahydro-2H- pyran-4- sulfonamide
1058131- 55-7
X1
165



 


S9 




benzyl 4- sulfamoylpiperidine- 1-carboxylate
287953- 54-2
X1
298



 


S10




3- morpholinopropane- 1-sulfonamide
1132- 61-2
X2 Specific example
208
209


 


S11




(2S)-2-(4- methylpiperazine- 1- carbonyl)pyrrolidine- 1-sulfonamide
15761- 39-4
X3 Specific example
276



 


S12




4-(4- methylpiperazine- 1- carbonyl)piperidine- 1-sulfonamide
1018826- 44-2
X4 Specific example
290



 


S13




3- fluoropynrolidine- 1-sulfonamide
7803- 58-9, 169750- 17-8
X4B
168



 


S14




3- methoxypyrrolidine- 1-sulfonamide
7803- 58-9, 136725- 50-3
X4B Specific example
180



 


S15




4- (methoxymethyl) piperidine-1- sulfonamide
1189- 71-5, 399580- 55-3
X5 Specific example
208



 


S16




piperidine-1- sulfonamide
1189- 71-5, 110-89- 4
X5
164



 


S17




3-fluoroazetidine- 1-sulfonamide
1189- 71-5, 617718- 46-4
X5
154



 


S18




azetidine-1- sulfonamide
1189- 71-5, 503-29- 7
X5
136



 


S19




(2R)-2- (methoxymethyl) pyrrolidine-1- sulfonamide
1181- 71-5, 84025- 81-0
X5
194



 


S20




N-oxan-4- ylsulfuric diamide
1189- 71-5, 38041- 19-9
X5
180



 


S21




N-methyl-N-oxan- 4-ylsulfuric diamide
1189- 71-5, 220641- 87-2
X5
194



 


S22




3,3- difluoroazetidine- 1-sulfonamide
1189- 71-5, 288315- 03-7
X5
172



 


S23




N-methoxysulfuric diamide
1189- 71-5, 593-56- 6
X5
126



 


S24




3-(morpholin-4- yl)pyrrolidine-1- sulfonamide
1189- 71-5, 53617- 37-1
X5
235



 


S25




4- cyclopropylpiperazine- 1-sulfonamide
1189- 71-5, 20327- 23-5
X5
205



 


S26




4-(2- methoxyethyl) piperazine-1- sulfonamide
1181- 71-5, 13484- 40-7
X5
223



 


S27




3- methoxyazetidine- 1-sulfonamide
1189- 71-5, 148644- 09-1
X5
166



 


S28




morpholine-4- sulfonamide
1189- 71-5, 110-91- 8
X5
166









Method Y1: Synthesis of Acylsulfonamide and Acylsulfamate from Carboxylic Acid




EDC.HCl (CAS 25952-538, 1.0 to 4.0 equiv) is added at RT to a stirring solution of carboxylic acid, sulfonamide or sulfamate (from 1.0 to 4.0 equiv) and 4-(dimethylamino) pyridine (CAS 1122-58-3, from 0.1 to 2.0 equiv) in dichloromethane or/and THF or/and acetone or/and acetonitrile. The reaction mixture is stirred at RT until full conversion is observed. The reaction mixture can be worked up or the solvent can be evaporated and the residue is purified by precipitation, by flash column chromatography or by preparative HPLC to yield the titled acylsulfonamide or acylsulfamide. To work up the reaction mixture, the solvent can be evaporated, and the residue is then partitioned between dichloromethane and water. The organic phase is successively washed with a saturated aqueous solution of NaHCO3, aqueous 0.5 N HCl and brine. The organic phase is separated, dried over sodium sulfate, filtered and concentrated in vacuo. Alternatively, the reaction mixture may be concentrated without an extractive workup. The residue is purified either by precipitation, by flash column chromatography or by preparative HPLC to yield the titled acylsulfonamide or acylsulfamate.
Alternatively, acylsulfonamides or acylsulfamates can be prepared in the following manner. A solution of the carboxylic acid (1 eq) in dichloromethane, dichloroethane or dimethylformamide can be treated with carbodiimidazole (1-2.5 eq) stirred at ambient temperature to 65° C. for from 0.5-3 hours. Then the sulfonamide or sulfamate (1-3 eq) and optional potassium bis(trimethylsilyl)amide, sodium hydride, or triethylamine followed by 1,8-diazabicycloundec-7-ene (1-3 eq) and optional 4-(dimethylamino)pyridine (1-2 eq) can be added, and the reaction mixture is stirred at 20-60° C. for 2-16 hours. The reaction mixture can then be concentrated and the residue purified.
Illustrative Synthesis of Compound 71: 4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-3-cyclobutyl-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide




EDC.HCl (CAS 25952-538, 24.6 g, 128.3 mmol) was added at RT to a stirring solution of intermediate A056 (30.7 g, 64.1 mmol), methanesulfonamide (CAS 3144-09-0, 12.2 g, 128.3 mmol) and 4-(dimethylamino) pyridine (CAS 1122-58-3, 3.1 g, 25.7 mmol) in DCM (1 L). The reaction mixture was stirred at RT for 1.5 hours. The solution was diluted with DCM (700 mL), washed successively with a saturated aqueous solution of sodium hydrogencarbonate (500 mL), aqueous 0.5 N HCl (500 mL) and a saturated aqueous solution of NaCl (500 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude sample was purified by flash column chromatography eluting with DCM/ethyl acetate. The compound was suspended in acetonitrile and refluxed until complete dissolution. The warm solution was poured in hot water (700 mL), and the mixture was refluxed for 2 hours. The reaction volume was reduced to one third under a flow of nitrogen at 80° C. The precipitate was collected by filtration and dried at 40° C. under reduced pressure.
Illustrative Synthesis of Compound 256: 3-cyclobutyl-N-(2-methoxyethanesulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide




To a 4 mL vial charged with stir bar was added 3-cyclobutyl-4-[4-(methoxymethyl)-1-piperidyl]-1-phenyl-pyrazolo[3,4-b]pyridine-6-carboxylic acid (A136, 40 mg, 0.095 mmol) dissolved in 600 μL of dichloroethane followed by carbodiimidazole (34 mg, 0.21 mmol) in 600 μL of dichloroethane. The mixture was stirred at 42° C. for two hours. Then 2-methoxyethanesulfonamide (40 mg, 3 eq, 0.28 mmol) was then added followed by 1,8-diazabicycloundec-7-ene (43 uL, 3 eq, 0.28 mmol). The resultant mixture was heated at 60° C. for 16 hours. After completion of reaction, the reaction mixture was concentrated, dissolved in DMSO, and purified by reverse phase HPLC (C18, 0-100% CH3CN/water (0.1% TFA)). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/min (0-0.5 min 10% A, 0.5-6.0 min linear gradient 10-100% A, 6.0-7.0 min 100% A, 7.0-8.0 min linear gradient 100-10% A) to afford the title compound.
Illustrative Synthesis of Compound 328: 3-cyclobutyl-N-(methanesulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide




3-Cyclobutyl-4-(4-morpholino-1-piperidyl)-1-phenyl-pyrazolo[3,4-b]pyridine-6-carboxylic acid (A268, 139 mg, 0.30 mmol) and carbonyl diimidazole (73 mg, 0.45 mmol) were stirred in anhydrous DMF (2 mL) at room temperature for 50 minutes. Then methanesulfonamide (57 mg, 0.60 mmol) was added, followed by triethylamine (125 μL, 0.90 mmol), and the suspension was stirred overnight. DBU (45 μL, 0.30 mmol) was added dropwise to the suspension, which was stirred for more than forty minutes before additional DBU (22.5 μL, 0.15 mmol) was added, and the solution was heated at 50° C. for more than 4 hours. The reaction mixture was then purified by preparative HPLC on a preparatory Waters® Atlantis® T3 column (30 mm×100 mm) with a 20 to 100% gradient of acetonitrile in 10 mM aqueous ammonium acetate at 40 mL/min to give the titled compound (70 mg).
Illustrative Synthesis of Compound 331: 3-cyclobutyl-N-(methanesulfonyl)-4-{4-[2-(morpholin-4-yl)ethyl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide




3-Cyclobutyl-4-[4-(2-morpholinoethyl)-1-piperidyl]-1-phenyl-pyrazolo[3,4-b]pyridine-6-carboxylic acid (A270, 118 mg, 0.24 mmol) and carbonyl diimidazole (78 mg, 0.48 mmol) were stirred in anhydrous DMF (1.5 mL) at room temperature for one hour. Then methanesulfonamide (46 mg, 0.48 mmol) and triethylamine (67 μL, 0.48 mmol) were added, followed by slow, dropwise addition of DBU (54 μL, 0.36 mmol). The reaction mixture was stirred for about another 30 minutes, diluted with water (8 mL), concentrated and purified by preparative HPLC on a preparatory Waters® Atlantis® T3 column (30 mm×100 mm) with a 20 to 100% gradient of acetonitrile in 10 mM aqueous ammonium acetate at 40 mL/min to give the titled compound (46 mg).
Illustrative Synthesis of Compound 332: 4-[(3aR,7aS)-1-acetyloctahydro-5H-pyrrolo[3, 2-c]pyridin-5-yl]-3-cyclobutyl-N-[3-(morpholin-4-yl)propane-1-sulfonyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide




4-[(3aR,7aS)-1-Acetyl-3,3a,4,6,7,7a-hexahydro-2H-pyrrolo[3,2-c]pyridin-5-yl]-3-cyclobutyl-1-phenyl-pyrazolo[3,4-b]pyridine-6-carboxylic acid (A271, <0.5 mmol) and carbonyl diimidazole (243 mg, 1.5 mmol) were stirred in anhydrous DMF (4 mL) at room temperature for an hour. Then triethylamine (210 μL, 1.5 mmol) and a solution of 3-(morpholin-4-yl)propane-1-sulfonamide (S10, 313 mg, 1.5 mmol) in anhydrous acetonitrile (400 μL) were added, followed by slow dropwise addition of DBU (75 μL, 0.50 mmol). The reaction mixture was stirred for an hour, more DBU (45 μL, 0.30 mmol) was added dropwise, and the reaction mixture was stirred another hour before being diluted with water (20 mL), concentrated and purified by preparative HPLC on a preparatory Waters® Atlantis® T3 column (30 mm×100 mm) with a 5 to 100% gradient of acetonitrile in 10 mM aqueous ammonium acetate at 40 mL/min to give the titled compound (74 mg).
Illustrative Synthesis of Compound 347: 3-cyclobutyl-N-[3-(morpholin-4-yl)propane-1-sulfonyl]-4-[(oxan-4-yl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide




3-Cyclobutyl-1-phenyl-4-(tetrahydropyran-4-ylmethoxy)pyrazolo[3,4-b]pyridine-6-carboxylic acid (A148, 102 mg, 0.25 mmol) and carbonyl diimidazole (61 mg, 0.38 mmol) were stirred in anhydrous DMF (1.6 mL) at room temperature for one hour. Then a solution of 3-(morpholin-4-yl)propane-1-sulfonamide (S10, 104 mg, 0.50 mmol) in DMF (0.4 mL) and triethylamine (70 μL, 0.50 mmol) were added, followed by slow, dropwise addition of DBU (56 L, 0.37 mmol). The reaction mixture was stirred for another thirty minutes, diluted with water (8 mL), concentrated and purified by preparative HPLC on a Waters® Atlantis® T3 column (30 mm×100 mm) with a 30 to 60% gradient of acetonitrile in 10 mM aqueous ammonium acetate at 50 mL/min to give the titled compound (61 mg).
Illustrative Synthesis of Compound 349: 3-cyclobutyl-4-[(3R)-3-(hydroxymethyl)piperidin-1-yl]-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide




3-Cyclobutyl-4-[(3R)-3-(hydroxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid (A284, 57 mg, 0.14 mmol) and carbonyl diimidazole (46 mg, 0.28 mmol) were stirred in anhydrous DMF (1.0 mL) at room temperature for about one hour. Then methanesulfonamide (27 mg, 0.28 mmol) and triethylamine (39 μL, 0.28 mmol) were added, followed by slow, dropwise addition of DBU (31.5 μL, 0.21 mmol). The reaction mixture was stirred more than 30 minutes, diluted with water (8 mL), concentrated and purified by preparative HPLC on a Waters® Atlantis® T3 C18 column (30×150 mm) with a 30 to 60% gradient of acetonitrile in 10 mM aqueous ammonium acetate at 50 mL/min to give the titled compound (17 mg).
Illustrative Synthesis of Compound 350: 3-cyclobutyl-4-[(3R)-3-(hydroxymethyl)piperidin-1-yl]-N-[3-(morpholin-4-yl)propane-1-sulfonyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide




3-Cyclobutyl-4-[(3R)-3-(hydroxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid (A284, 61 mg, 0.15 mmol) and carbonyl diimidazole (49 mg, 0.30 mmol) were stirred in anhydrous DMF (1.0 mL) at room temperature for about one hour. Then a solution of 3-(morpholin-4-yl)propane-1-sulfonamide (S10, 63 mg, 0.30 mmol) in anhydrous acetonitrile (200 μL) and triethylamine (42 μL, 0.30 mmol) were added, followed by slow, dropwise addition of DBU (34 μL, 0.23 mmol). The reaction mixture was stirred for more than 30 minutes, diluted with water (8 mL), concentrated and purified by preparative HPLC on a Waters® Atlantis® T3 C18 column (30×150 mm) with a 40 to 70% gradient of acetonitrile in 10 mM aqueous ammonium acetate at 50 mL/min to the titled compound (30 mg).
Illustrative Synthesis of Compound 365: 4-([1,4′-bipiperidin]-1′-yl)-3-cyclobutyl-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide




3-Cyclobutyl-1-phenyl-4-[4-(1-piperidyl)-1-piperidyl]pyrazolo[3,4-b]pyridine-6-carboxylic acid (A081, 51 mg, 0.11 mmol) and carbonyl diimidazole (28 mg, 0.17 mmol) were stirred in anhydrous DMF (600 μL) at room temperature for an hour. Then methanesulfonamide (21 mg, 0.22 mmol) and triethylamine (31 μL, 0.22 mmol) were added, followed by DBU (25.5 μL, 0.17 mmol). The reaction mixture was stirred 30 minutes at room temperature, diluted with water (5 mL), concentrated and purified by preparative HPLC on a Waters® SunfireTM C8 column (30×150 mm) with a 30 to 60% gradient of acetonitrile in 10 mM aqueous ammonium acetate at 50 mL/min to give the titled compound (30 mg).
Illustrative Synthesis of Compound 411: 1-(4-fluorophenyl)-N-(methanesulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide




1-(4-Fluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid (A408, 70 mg, 0.15 mmol) and carbonyl diimidazole (37 mg, 0.23 mmol) were stirred in anhydrous DMF (800 μL) at room temperature for an hour. Then methanesulfonamide (29 mg, 0.30 mmol) and triethylamine (42 μL, 0.30 mmol) were added, followed by slow addition of DBU (34 μL, 0.23 mmol). The reaction mixture was stirred 30 minutes at room temperature, diluted with methanol and purified by preparative HPLC on a Waters® SunfireTM C8 column (30×150 mm) with a 30 to 60% gradient of acetonitrile in 10 mM aqueous ammonium acetate to give the titled compound.
Illustrative Synthesis of Compound 413: N-(ethanesulfonyl)-1-(4-fluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide




1-(4-Fluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid (A408, 70 mg, 0.15 mmol) and carbonyl diimidazole (37 mg, 0.23 mmol) were stirred in anhydrous DMF (800 μL) at room temperature for an hour. Then ethanesulfonamide (33 mg, 0.30 mmol) and triethylamine (42 μL, 0.30 mmol) were added, followed by slow addition of DBU (34 μL, 0.23 mmol). The reaction mixture was stirred 30 minutes at room temperature, diluted with methanol and purified by preparative HPLC on a Waters® SunfireTM C8 column (30×150 mm) with a 30 to 60% gradient of acetonitrile in 10 mM aqueous ammonium acetate to give the titled compound.
Illustrative Synthesis of Compound 414: N-(cyclopropanesulfonyl)-1-(4-fluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide




1-(4-Fluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid (A408, 70 mg, 0.15 mmol) and carbonyl diimidazole (37 mg, 0.23 mmol) were stirred in anhydrous DMF (800 μL) at room temperature for an hour. Then cyclopropanesulfonamide (36 mg, 0.30 mmol) and triethylamine (42 μL, 0.30 mmol) were added, followed by slow addition of DBU (34 μL, 0.23 mmol). The reaction mixture was stirred 30 minutes at room temperature, diluted with methanol and purified by preparative HPLC on a Waters® SunfireTM C8 column (30×150 mm) with a 30 to 60% gradient of acetonitrile in 10 mM aqueous ammonium acetate to give the titled compound.
Illustrative Synthesis of Compound 427: 4-([1,4′-bipiperidin]-1′-yl)-3-cyclobutyl-N-(ethanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide




3-Cyclobutyl-1-phenyl-4-[4-(1-piperidyl)-1-piperidyl]pyrazolo[3,4-b]pyridine-6-carboxylic acid (A081, 92 mg, 0.20 mmol) and carbonyl diimidazole (49 mg, 0.30 mmol) were stirred in anhydrous DMF (1.0 mL) at room temperature for 90 minutes. Then ethanesulfonamide (44 mg, 0.40 mmol) and triethylamine (56 μL, 0.40 mmol) were added, followed nearly 15 minutes later by slow addition DBU (45 μL, 0.30 mmol). The reaction mixture was stirred 30 minutes at room temperature, diluted with methanol and purified by preparative HPLC on a Waters® SunfireTM C8 column (30×150 mm) with a 40 to 70% gradient of acetonitrile in 10 mM aqueous ammonium acetate to give the titled compound.
Illustrative Synthesis of Compound 428: 4-([1,4′-bipiperidin]-1′-yl)-3-cyclobutyl-N-(cyclopropanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide




3-Cyclobutyl-1-phenyl-4-[4-(1-piperidyl)-1-piperidyl]pyrazolo[3,4-b]pyridine-6-carboxylic acid (A081, 92 mg, 0.20 mmol) and carbonyl diimidazole (49 mg, 0.30 mmol) were stirred in anhydrous DMF (1.0 mL) at room temperature for 90 minutes. Then cyclopropanesulfonamide (49 mg, 0.40 mmol) and triethylamine (56 μL, 0.40 mmol) were added, followed nearly 15 minutes later by slow addition DBU (45 μL, 0.30 mmol). The reaction mixture was stirred 30 minutes at room temperature, diluted with methanol and purified by preparative HPLC on a Waters® SunfireTM C8 column (30×150 mm) with a 30 to 60% gradient of acetonitrile in 10 mM aqueous ammonium acetate to give the titled compound.
Illustrative Synthesis of Compound 454: 4-([1,4′-bipiperidin]-1′-yl)-3-cyclobutyl-N-[3-(morpholin-4-yl)propane-1-sulfonyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide




To a suspension of the 3-cyclobutyl-1-phenyl-4-[4-(1-piperidyl)-1-piperidyl]pyrazolo[3,4-b]pyridine-6-carboxylic acid (46 mg, 0.10 mmol, A081) and carbonyl diimidazole (29 mg, 0.18 mmol) in anhydrous DMF (400 μL) was added pyridine (81 μL, 1.0 mmol). The mixture was stirred nearly ten minutes at room temperature and then another 15 minutes at 50° C. before being brought to room temperature. In a separate vial, 3-morpholinopropane-1-sulfonamide (42 mg, 0.20 mmol) under nitrogen was dissolved into anhydrous DMF (400 μL) and treated with 1 M potassium bis(trimethylsilyl)amide in THF (190 μL, 0.19 mmol), stirred ten minutes to give a suspension and then treated dropwise with the contents of the first vial, which were transferred with a DMF (200 μL) rinse. The mixture was stirred at room temperature for three days, diluted with methanol and purified by preparative HPLC on a Waters® SunfireTM C8 column (30×150 mm) with a 35 to 65% gradient of acetonitrile in 10 mM aqueous ammonium acetate to give the titled compound.
Illustrative Synthesis of Compound 658: 3-cyclobutyl-N-(ethanesulfonyl)-N-methyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide




3-Cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid (45 mg, 0.10 mmol, A409) dissolved in dichloromethane (500 μL) was treated with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (18 mg, 0.12 mmol) in dichloromethane (500 μL), dimethylamino pyridine (24 mg, 0.2 mmol) and N-methylethanesulfonamide (13 mg, 0.11 mmol). The mixture was then stirred at room temperature overnight. The mixture was concentrated, and the residue was dissolved DMSO and purified by reverse phase HPLC (C18, 0-100% CH3CN/water (0.1% TFA)). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/minute (0-0.5 minute 10% A, 0.5-6.0 minutes linear gradient 10-100% A, 6.0-7.0 minutes 100% A, 7.0-8.0 minutes linear gradient 100-10% A) gave the titled compound.
Method Y2: Synthesis of Acylsulfonamide
Synthesis of Compounds 289 & 298: 3-({3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carbonyl}sulfamoyl)propanoic acid and 3-cyclobutyl-N-[3-(dimethylamino)-3-oxopropane-1-sulfonyl]-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide




Step 1: 3-({3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carbonyl}sulfamoyl)propanoic acid
A solution of LiOH (0.0189 g, 0.45 mmol, 2.1 equiv) in H2O (1 mL) was added to a solution of compound 288 (0.123 g, 0.216 mmol) in THF. The reaction mixture was stirred for 30 min and then concentrated. The residue was partitioned between dichloromethane (100 mL) and an aqueous H3PO4/NaH2PO4 buffer (1.0 M, pH 2, 100 mL). The organic phase was washed with brine, dried over MgSO4, filtered and concentrated to give compound 289 (carboxylic acid).
Step 2: 3-cyclobutyl-N-[3-(dimethylamino)-3-oxopropane-1-sulfonyl]-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide
BOP (CAS: 56602-33-6, 0.037 g, 0.084 mmol, 1.2 equiv) was added to a solution of compound 289 (0.0378 g, 0.0680 mmol) in dichloromethane (4 mL). After 10 minutes, a THF solution of dimethylamine (2.0 M, 0.25 mL, 0.50 mmol, 7.3 equiv) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was charged onto a column of silica gel and eluted with CH2Cl2/iPrOH (20:1) to yield the titled compound. 1H NMR (400 MHz, CDCl3/CD3OD) δ ppm 7.99 (d, J=8.25, 2H), 7.51 (t, J=8.0 Hz, 2H), 7.44 (s, 1H), 7.32 (t, J=7.4, 1H), 3.98 (pent, J=8.4 Hz, 1H), 3.67-3.59 (m, 2H), 3.50 (t, J=6.5 Hz, 2H), 3.40-3.33 (m, 2H), 3.37 (s, 3H), 3.14 (t, J=6.5 Hz, 2H), 2.94-2.84 (m, 2H), 2.6-2.49 (m, 2H), 2.44-2.34 (m, 2H), 2.38 (s, 6H), 2.12-1.79 (m, 5H), 1.60-1.48 (m, 2H)
Method Y3: Synthesis of Acylsulfonamide




Potassium iodide (0.3 equiv) is added to a solution of alkylchloride in acetonitrile. The amine (15 to 20 equiv) is added, and the vial is sealed. The reaction mixture is stirred at RT or 50° C. for 16 hours. After concentration, the residue is partitioned between water and dichloromethane. The organic phase is washed with brine, dried over MgSO4, filtered and concentrated in vacuo. If necessary, the residue was purified either by precipitation in pentane or by silica gel chromatography.
Illustrative Synthesis of Compound 290: N-[3-(dimethylamino)propane-1-sulfonyl]-1-(4-fluorophenyl)-4-[4-(methoxymethyl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide




KI (2 mg, 0.012 mmol, 0.3 equiv) was added to a solution of N-(3-chloropropylsulfonyl)-1-(4-fluorophenyl)-3-isopropyl-4-[4-(methoxymethyl)-1-piperidyl]pyrazolo[3,4-b]pyridine-6-carboxamide (AC01, 20 mg, 0.035 mmol) in acetonitrile (3 mL). The vial was sealed, and the reaction mixture was saturated with gaseous dimethylamine. The reaction mixture was stirred at RT for 16 hours. After concentration, the residue was partitioned between water and dichloromethane. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated to give the titled compound.
Method Y4: Synthesis Via Carboxamide




Step 1
Oxalyl chloride (0.40 mL, 4.7 mmol, 9.6 equiv) and a drop of dimethylformamide are added to a solution of carboxylic acid (0.49 mmol) in dichloromethane (2 mL). After effervescence has ceased, the vial is sealed, and the reaction mixture is stirred at room temperature for 1 hour. The reaction mixture is concentrated in vacuo, and to the residue is added a dioxane solution of ammonia (0.5 M, 10.0 mL, 5.0 mmol, 10 equiv). After 1 hour, volatiles are then removed via rotary evaporation. The residue is purified by silica gel chromatography (dichloromethane/ethyl acetate, 4:1) to give the intermediate carboxamide.
Step 2
NaH (60% in mineral oil, 21 equiv to 50 equiv) is added to a solution of carboxamide in dry THF. After effervescence has ceased, sulfonyl chloride (1.4 to 2.0 equiv) is added. The reaction mixture is stirred at room temperature for several hours. An aqueous solution of malate buffer (1.0 M sodium malate/disodium malate, pH 4.5, 4 mL) is slowly added. After 5 minutes, the mixture is combined with chloroform or dichloromethane and stirred. The organic phase is collected and concentrated in vacuo. The residue is purified by preparative HPLC or by flash column chromatography to give the titled compound.
Illustrative Synthesis of Compound 287: 3-cyclobutyl-N-(3,5-dimethyl-1,2-oxazole-4-sulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide




Step 1
Oxalyl chloride (0.40 mL, 4.7 mmol, 9.6 equiv) and a drop of dimethylformamide were added to a solution of A136 (0.207 g, 0.49 mmol) in dichloromethane (2 mL). After effervescence had ceased, the vial was sealed, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, and to the residue was added a dioxane solution of ammonia (0.5M, 10.0 mL, 5.0 mmol, 10 equiv). After 1 hour, volatiles were then removed via rotary evaporation. The residue was purified by silica gel chromatography (CH2Cl2/EtOAc, 4:1) to give 3-cyclobutyl-4-[4-(methoxymethyl)-1-piperidyl]-1-phenyl-pyrazolo[3,4-b]pyridine-6-carboxamide.
Step 2
NaH (60% in mineral oil, 0.080 g, 2.0 mmol, 21 equiv) was added to a solution of 3-cyclobutyl-4-[4-(methoxymethyl)-1-piperidyl]-1-phenyl-pyrazolo[3,4-b]pyridine-6-carboxamide (0.041 g, 0.098 mmol) in dry THF (2 mL). After effervescence has ceased, 3,5-dimethylisoxazole-4-sulfonyl chloride (CAS: 877861-76-2, 0.038 g, 0.19 mmol, 1.9 equiv) was added. The reaction mixture was stirred at room temperature for 16 h. An aqueous solution of malate buffer (1.0 M sodium malate/disodium malate, pH 4.5, 4 mL) was slowly added. After 5 minutes, the mixture was combined with chloroform and agitated. The organic phase was collected and concentrated in vacuo. The residue was purified by preparative HPLC to give the titled compound.
Method Y5: Synthesis of Acylsulfonamide or Acylsulfamide from a Carboxylic Acid Chloride




Oxalyl chloride (CAS 79-37-8, 1.5 equiv) and 3 drops of dimethylformamide are added at 0° C. to a solution of carboxylic acid in dichloromethane. After 1 h of stirring at room temperature, additional oxalyl chloride (CAS 79-37-8, 1.5 equiv) is added. After 30 minutes of stirring, the reaction mixture is cooled to 0° C. and sulfonamide (3.0 equiv) followed by triethylamine (2.0 equiv) are added. The reaction mixture is stirred at room temperature for 3 h and then concentrated in vacuo. The residue is partitioned between a saturated aqueous solution of sodium hydrogencarbonate and dichloromethane. The organic phase is dried over MgSO4, filtered and concentrated in vacuo. The residue dissolved in dichloromethane is precipitated by addition to a mixture of diethyl ether/pentane. The solid collected by filtration is purified by silica gel chromatography to give the titled compound.
Alternatively, oxalyl chloride (5-10 equivalents) is added to a mixture of carboxylic acid (1 equiv) in dichloromethane followed by stirring at ambient temperature over 8-24 hours. The reaction mixture is diluted with dichloromethane and concentrated several times followed by drying under vacuum. The carboxylic acid chloride (1 equiv) is then combined with sulfonamide (2 equiv) and triethylamine (2.5-5 equiv) in dichloromethane with stirring at ambient temperature over 1-24 hours. The reaction mixture is concentrated and purified by preparative HPLC.
Illustrative Synthesis of Compound 3: 3-methyl-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-N-(trifluoromethanesulfonyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide




Oxalyl chloride (CAS 79-37-8, 0.012 mL, 0.15 mmol, 1.5 equiv) and 3 drops of dimethylformamide were added at 0° C. to a solution of A002 (41 mg, 0.1 mmol) in dichloromethane (2 mL). After 1 h of stirring at room temperature, additional oxalyl chloride (CAS 79-37-8, 0.012 mL, 0.15 mmol, 1.5 equiv) was added. After 30 minutes of stirring, the reaction mixture was cooled to 0° C. and trifluoromethanesulfonamide (CAS 421-85-2, 48 mg, 0.3 mmol, 3.0 equiv) followed by triethylamine (0.029 mL, 0.2 mmol, 2.0 equiv) were added. The reaction mixture was stirred at room temperature for 3 h and then concentrated in vacuo. The residue was partitioned between a saturated aqueous solution of sodium hydrogencarbonate and dichloromethane. The organic phase was dried over MgSO4, filtered and concentrated. The residue dissolved in dichloromethane was precipitated by addition to a mixture of diethyl ether/pentane. The solid collected by filtration was purified by silica gel chromatography (heptane/EtOAc 100/0 to 0/100) to give the titled compound.
Illustrative Synthesis of Compound 383: 3-cyclobutyl-N-(morpholine-4-sulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide




A suspension of 3-cyclobutyl-4-(4-morpholino-1-piperidyl)-1-phenyl-pyrazolo[3,4-b]pyridine-6-carboxylic acid (A268, 0.0511 g, 0.111 mmol) and (COCl)2 (18 μL, 0.206 mmol) in CH2Cl2 (0.40 mL) with catalytic DMF was stirred for 90 minutes, concentrated, and re-dissolved in CH2Cl2 (0.40 mL). To this mixture was added morpholine-4-sulfonamide (0.0213 g, 0.128 mmol), DMAP (0.0141 g, 0.115 mmol), and triethylamine (18 μL, 0.129 mmol), and the mixture was stirred overnight. The reaction mixture was then diluted with saturated NaHCO3, extracted with CH2Cl2, concentrated, and chromatographed on silica gel (25% acetone/CH2Cl2) and re-chromatographed (2.5% CH3OH/CH2Cl2) and precipitated (methanol/methyl tert-butyl ether) to give the titled compound (0.0267 g, 0.044 mmol, 40% yield).
Illustrative Synthesis of Compound 432: 3-cyclobutyl-N-[methyl(propyl)sulfamoyl]-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide




A vial was charged with 3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carbonyl chloride (35 mg, 0.08 mmol, prepared as described below for the synthesis of compound 437) dissolved in 500 μL of dichloromethane followed by N-methyl-N-propylsulfonamide (2 eq, 0.15 mmol) in 500 μL of dichloromethane and neat triethylamine (38 μL, 4 eq, 0.32 mmol). The mixture was then stirred at room temperature for one hour. After completion of reaction, the mixture was concentrated, and the residue was dissolved in DMSO and purified by reverse phase HPLC (C18, 0-100% CH3CN/water (0.1% TFA)). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/minute (0-0.5 minute 10% A, 0.5-6.0 minutes linear gradient 10-100% A, 6.0-7.0 minutes 100% A, 7.0-8.0 minutes linear gradient 100-10% A) to afford the title compound.
Illustrative Synthesis of Compound 437: 3-cyclobutyl-N-(ethanesulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide




To a suspension of 3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid (A409, 0.8117 g, 1.759 mmol) in dichloromethane (10 mL) was added oxalyl chloride (1 mL, 11.4 mmol) dropwise, and the mixture was stirred at RT overnight. The reaction mixture was diluted with more dichloromethane (11 mL) and concentrated under vacuum. This process was repeated two additional times. The resultant yellow solid material, which was kept under vacuum for one hour to give 3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carbonyl chloride.
To a suspension of 3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carbonyl chloride (0.050 g, 0.104 mmol) in dichloromethane (1.5 mL) was added ethanesulfonamide (0.023 g, 0.208 mmol) and triethylamine (0.051 mL, 0.365 mmol), and the mixture was stirred at RT for overnight. The reaction mixture was concentrated under vacuum and purified by preparative HPLC on a Waters® SunfireTM C8 column (30×150 mm) with an escalating gradient of acetonitrile in 10 mM aqueous ammonium acetate to the titled compound.
Method Y6: Protecting Group Removal
Protecting groups, known to one of skill in the art can be removed using appropriate procedures known to remove such protecting groups. Specific illustrations for select protecting group removal are provided in the examples below.
Benzyl Ether Removal
Illustrative Synthesis of Compound 366: 3-cyclobutyl-N-(2-hydroxyethanesulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide




A solution of AC05 (8 mg, 0.013 mmol) in THF (5 mL) was degassed with nitrogen. Palladium hydroxide (2 mg, 25% w/w) was added, and the reaction mixture was stirred under hydrogen atmosphere (balloon) for 3 hours. The reaction mixture was then filtered on Dicalite® diatomaceous earth, and the filtrate was concentrated in vacuo. The residue dissolved in dichloromethane (1 mL) was precipitated by addition to heptane. The collected solid was dried in vacuo to yield the titled compound.
Illustrative Synthesis of Compound 105: 1-[3-(3-hydroxyazetidin-1-yl)phenyl]-N-(methanesulfonyl)-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide




A solution of AC02 (38 mg, 0.06 mmol) in a mixture of EtOH/THF (1/2 mL) was degassed with nitrogen. 10% Pd/C (5 mg) was added. The reaction mixture was degassed with H2 for 5 min, and then was stirred for 48 hours at room temperature under hydrogen atmosphere (balloon). Additional 10% Pd/C (5 mg) was added, and the reaction mixture was stirred for 18 hours at room temperature under hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC to give the titled compound.
Benzyl Carbamate Removal
Illustrative Synthesis of Compound 368: 3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-N-(piperidine-4-sulfonyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide




A solution of AC03 (60 mg, 0.09 mmol) in ethanol (10 mL) was degassed with nitrogen. Palladium hydroxide (15 mg, 25% w/w) was added, and the reaction mixture was stirred at RT under hydrogen atmosphere (balloon) for 16 hours. The reaction mixture was filtered, and the cake washed with THF, MeOH and chloroform. The filtrate was concentrated in vacuo. The residue dissolved in dichloromethane was precipitated by addition to a mixture of diethyl ether and pentane. The obtained solid was dried in vacuo to yield the titled compound.
Phthalimide Removal
Illustrative Synthesis of Compound 261: N-(2-aminoethanesulfonyl)-3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide




Hydrazine hydrate (50-60% in water, 0.015 mL, 0.2 mmol, 6.7 equiv) was added to a solution of 3-cyclobutyl-N-[2-(1,3-dioxoisoindolin-2-yl)ethylsulfonyl]-4-[4-(methoxymethyl)-1-piperidyl]-1-phenyl-pyrazolo[3,4-b]pyridine-6-carboxamide (compound 260, 20 mg, 0.03 mmol) in ethanol (3 mL). The reaction mixture was refluxed for 3 hours and then concentrated in vacuo. The residue was partitioned between a saturated aqueous solution of sodium hydrogencarbonate and dichloromethane. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (dichloromethane/acetone 95/5 to 85/15) to give the titled compound.
Tert-Butyl Carbamate Removal
Illustrative Synthesis of Compound 258: 4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-N-(methanesulfonyl)-1-phenyl-3-[(piperidin-4-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide




Trifluoroacetic acid (0.1 mL, 1.0 mmol, 23 equiv) was added to a solution of tert-butyl 4-[4-[6-(4-cyano-1-piperidyl)-3-pyridyl]-6-(methylsulfonylcarbamoyl)-1-phenyl-pyrazolo[3,4-b]pyridin-3-yl]oxypiperidine-1-carboxylate (compound 259, 30 mg, 0.043 mmol) in dichloromethane (1 mL). The reaction mixture was stirred at room temperature until completion of the reaction. The reaction mixture was quenched with a saturated solution of sodium bicarbonate. The obtained precipitate was collected by filtration, washed with water and dried to yield the titled compound.
Illustrative Synthesis of Compound 631: 1-cyclohexyl-4-[4-(hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carbonyl)phenyl]-N-(methanesulfonyl)-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide




AC15 (18 mg, 26 μmol) was dissolved in dichloromethane (5 mL) and 4 M HCl in dioxane (0.5 mL, 2 mmol) was added. The solution was stirred at room temperature for two hours and then concentrated in vacuo. The residue was suspended in DCM and washed with a phosphate buffer solution (pH 6.2). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the titled compound.
Method Y7: Azide Displacement of Alkyl Halide
Synthesis of Compound 327: 4-(4-azidophenyl)-N-(3-azidopropane-1-sulfonyl)-1-[3-(dimethylamino)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide




AC06 (160 mg, 0.275 mmol, 1 equiv) in anhydrous DMSO (2 mL) at RT under nitrogen atmosphere was added sodium azide (CAS 26628-22-8, 36 mg, 0.550 mmol, 2.0 equiv). The reaction mixture was stirred at 80° C. for 1 h. Then the reaction mixture was cooled down, diluted with dichloromethane, washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting crude mixture was purified by preparative HPLC to afford the titled compound.
Method Y8: Synthesis of Acylsulfamide




EDC.HCl (CAS 25952-538, 1.0 to 4.0 equiv) is added at RT to a stirring solution of carboxylic acid, sulfamide (from 1 to 4.0 equiv) and 4-(dimethylamino) pyridine (CAS 1122-58-3, from 0.2 to 2 equiv) in dichloromethane or/and THF or/and acetonitrile. The reaction mixture is stirred at RT until complete conversion. The solvent can be evaporated under reduced pressure. The residue can be worked up or purified by preparative HPLC. The work up consists in dissolving the sample in DCM and washing it with water and/or a saturated aqueous solution of NaHCO3. The organic phase is separated, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified either by flash column chromatography or by preparative HPLC to yield the titled compound.
Alternatively, acylsulfamides can be prepared in the following manner. A solution of the carboxylic acid (1 eq) in dichloromethane, dichloroethane or dimethylformamide can be treated with carbodiimidazole (1-2.5 eq) stirred at ambient temperature to 65° C. for 0.5-3 hours. Then the sulfamide (1-3 eq) and optional potassium bis(trimethylsilyl)amide or triethylamine followed by 1,8-diazabicycloundec-7-ene (1-3 eq) and optional 4-(dimethylamino)pyridine (1-2 eq) can be added, and the reaction mixture is stirred at 20-60° C. for 2-16 hours. The reaction mixture can then be concentrated or extractively worked up. The residue can be purified by precipitation, silica gel flash chromatography, or preparative HPLC.
Illustrative Synthesis of Compound 379: 3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-{4-[2-(methoxymethyl)morpholin-4-yl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide




EDC.HCl ([25952-538], 58 mg, 0.46 mmol) was added at RT to a stirred solution of A286 (120 mg, 0.23 mmol), N,N-dimethylsulfamide (58 mg, 0.46 mmol) and 4-(dimethylamino) pyridine (CAS 1122-58-3, 58 mg, 0.46 mmol) in a mixture of dichloromethane/acetonitrile (1:1, 4 mL). The reaction mixture was stirred at RT for 20 hours. The solvent was evaporated at 40° C. under a nitrogen flow. The residue was purified by preparative HPLC to yield the titled compound as formate salt.
Illustrative Synthesis of Compound 380: 3-cyclobutyl-N-(morpholine-4-sulfonyl)-1-phenyl-4-{4-[(pyrrolidin-1-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide




A suspension of 3-cyclobutyl-1-phenyl-4-{4-[(pyrrolidin-1-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid (A285, 0.1498 g, 0.326 mmol) and carbonyl diimidazole (0.0795 g, 0.490 mmol) in dimethylformamide (DMF) (1.0 mL) was stirred for 2.5 hours, and then morpholine-4-sulfonamide (0.0815 g, 0.490 mmol, [25999-04-6]), DMAP (0.0444 g, 0.363 mmol), and DBU (0.075 mL, 0.498 mmol) were added. The resultant mixture was stirred overnight. The reaction mixture was then diluted with water (10 mL), extracted with dichloromethane (3×8 mL), dried (Na2SO4), and chromatographed (7% CH3OH/CH2Cl2) and triturated (10 volumes methyl tert-butyl ether/5 volumes methanol) to give the titled compound (0.0602 g, 0.099 mmol, 30% yield).
Illustrative Synthesis of Compound 388: 3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-N-[4-(pyrrolidin-1-yl)piperidine-1-sulfonyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide




A 4-mL vial was charged with 3-cyclobutyl-4-[4-(methoxymethyl)-1-piperidyl]-1-phenyl-pyrazolo[3,4-b]pyridine-6-carboxylic acid (A136, 35 mg, 0.09 mmol) dissolved in 600 μL of dichloroethane followed by carbonyldiimidazole (27 mg, 0.18 mmol) in 600 μL of dichloroethane, and the mixture was stirred at 40° C. for two hours. To this mixture was then added 4-(pyrrolidin-1-yl)piperidine-1-sulfonamide (40 mg, 3 eq, 0.28 mmol) followed by 1,8-diazabicycloundec-7-ene (42 μL, 3 eq, 0.28 mmol), and the mixture was heated at 60° C. for 16 hours. The mixture was concentrated, and the residue was dissolved in DMSO and purified by reverse phase HPLC (C18, 0-100% CH3CN/water (0.1% TFA)). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/minute (0-0.5 minute 10% A, 0.5-6.0 minutes linear gradient 10-100% A, 6.0-7.0 minutes 100% A, 7.0-8.0 minutes linear gradient 100-10% A) to afford the title compound.
Illustrative Synthesis of Compound 412: N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide




1-(4-Fluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid (A408, 70 mg, 0.15 mmol) and carbonyl diimidazole (37 mg, 0.23 mmol) were stirred in anhydrous DMF (800 μL) at room temperature for an hour. Then N,N-dimethylsulfamide (37 mg, 0.30 mmol) and triethylamine (42 μL, 0.30 mmol) were added, followed by slow addition of DBU (34 μL, 0.23 mmol). The reaction mixture was stirred 30 minutes at room temperature, diluted with methanol and purified by preparative HPLC on a Waters® SunfireTM C8 column (30×150 mm) with a 40 to 70% gradient of acetonitrile in 10 mM aqueous ammonium acetate to give the titled compound.
Illustrative Synthesis of Compound 426: 4-([1,4′-bipiperidin]-1′-yl)-3-cyclobutyl-N-(dimethylsulfamoyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide




3-Cyclobutyl-1-phenyl-4-[4-(1-piperidyl)-1-piperidyl]pyrazolo[3,4-b]pyridine-6-carboxylic acid (A081, 92 mg, 0.20 mmol) and carbonyl diimidazole (49 mg, 0.30 mmol) were stirred in anhydrous DMF (1.0 mL) at room temperature for 90 minutes. Then N,N-dimethylsulfamide (50 mg, 0.40 mmol) and triethylamine (56 μL, 0.40 mmol) were added, followed nearly 15 minutes later by slow addition DBU (45 μL, 0.30 mmol). The reaction mixture was stirred 30 minutes at room temperature, diluted with methanol and purified by preparative HPLC on a Waters® SunfireTM C8 column (30×150 mm) with a 30 to 60% gradient of acetonitrile in 10 mM aqueous ammonium acetate to give the titled compound.
Illustrative Synthesis of Compound 652: 3-cyclobutyl-1-[3-(difluoromethoxy)phenyl]-N-(dimethylsulfamoyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide




A solution of 3-cyclobutyl-1-[3-(difluoromethoxy)phenyl]-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid (0.0536 g, 0.102 mmol, A410) and 1,1′-carbonyldiimidazole (0.0253 g, 0.156 mmol) in N,N-dimethylformamide (DMF) (0.40 mL) was stirred at 60° C. for 1 hour. Then N,N-dimethylsulfamide (0.0192 g, 0.155 mmol), DMAP (0.0138 g, 0.113 mmol), and DBU (0.023 mL, 0.153 mmol) were added, and the mixture was stirred for 2.5 hours. The mixture was diluted with water (10 mL), extracted with DCM (4×8 mL), dried (Na2SO4), and concentrated. The residue was purified by chromatography on silica gel (0-3% isopropanol/DCM) to give the titled compound
Method Y9: De-benzylation




A vial is loaded with benzylated acylsulfonamide (1.0 equiv) and 10% Pd on charcoal (0.1 equiv). The vial is sealed, evacuated and back-filled with N2 and THF/MeOH 1:1 is added by syringe. The reaction mixture is evacuated and back-filled with H2 three times, and the reaction mixture is stirred overnight at 50° C. The mixture is filtered on a Pall-Seitz thick paper filter and concentrated in vacuo. The residue is dissolved in MeOH, filtered over a 0.45 μM plug filter and purified by means of semi-preparative HPLC (0.1% TFA in water/CH3CN). The compound is dissolved in DCM, 4 M HCl in dioxane is added, and the mixture was concentrated in vacuo to afford the debenzylated compound.
Illustrative Synthesis of Compound 517: 3-cyclobutyl-1-(4-fluorophenyl)-N-(methylsulfamoyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide




A vial was loaded with N-[benzyl(methyl)sulfamoyl]-3-cyclobutyl-1-(4-fluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide (AC16, 1.0 equiv., 0.151 mmol, 100 mg) and 10% Pd on charcoal (0.1 equiv., 0.015 mmol, 16 mg). The vial was sealed, evacuated and back-filled with N2, and THF/MeOH 1:1 (2 mL) was added by syringe. The reaction mixture was evacuated and back-filled with H2 three times, and the reaction mixture was stirred overnight at 50° C. The mixture was filtered on a Pall-Seitz thick paper filter and concentrated in vacuo. The residue was dissolved in MeOH, filtered over a 0.45 μM plug filter and purified by means of semi-preparative HPLC (0.1% TFA in water/CH3CN). The compound was dissolved in DCM, and then 4 M HCl in dioxane (0.1 mL) was added and the mixture was concentrated in vacuo to afford the titled compound.
Method Y10: Acylsulfonamide N-alkylation




An acylsulfonamide is treated with a C1-C6 alkyl halide or C1-C6 alkyl halide in the presence of a base such as but not limited to sodium bicarbonate or cesium carbonate in acetonitrile or N,N-dimethylformamide or a mixture thereof at room temperature to 70° C. over 8-60 hours. The reaction mixture is optionally quenched with water. The mixture may be optionally extractively worked up and concentrated or simply concentrated. The residue can be purified by precipitation, chromatography on silica gel, or by preparative HPLC to give the N-alkylated acylsulfonamide.
Illustrative Synthesis of Compound 656: 3-cyclobutyl-N-(methanesulfonyl)-N-methyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide




A mixture of 3-cyclobutyl-N-(methanesulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide dihydrochloride (0.0318 g, 0.052 mmol, compound 328), iodomethane (4.86 μl, 0.078 mmol), and Cs2CO3 (0.0506 g, 0.155 mmol) in N,N-dimethylformamide (DMF) (0.25 mL) was stirred at RT for 1 hour, and at 60° C. overnight. The mixture was then quenched with water, concentrated, and chromatographed on silica gel (5% MeOH/DCM) and re-chromatographed (15-25% acetone/DCM) to give the titled compound.
Illustrative Synthesis of Compound 657: 3-cyclobutyl-N-(methanesulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-N-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide




A mixture of 3-cyclobutyl-N-(methanesulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide (0.0508 g, 0.102 mmol, compound 185), iodomethane (10 μL, 0.161 mmol), and NaHCO3 (0.0265 g, 0.315 mmol) in acetonitrile (0.40 mL) was stirred at RT overnight. N,N-Dimethylformamide (DMF) (0.20 mL) was added, and the mixture was heated to 60° C. for 5 hours (little reaction). Then, additional iodomethane (10 μL, 0.161 mmol) and NaHCO3 (0.0265 g, 0.315 mmol) were added, and the mixture was stirred at 60° C. overnight. The mixture was diluted with water, extracted with DCM, dried (Na2SO4), and chromatographed on silica gel (2% EtOAc/DCM) to give the titled compound.
Synthesis of Compound 386: N-(2-acetamidoethanesulfonyl)-3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-




A solution of AC08 (42 mg, 0.06 mmol) in a mixture of THF (6 mL) and acetic anhydride (0.1 mL, 1.0 mmol) was degassed with nitrogen. 10% Pd/C (9 mg, 0.008 mmol) was added and the reaction mixture was purged with H2. The mixture was stirred for 16 hours at RT under a hydrogen atmosphere (balloon). The reaction mixture was filtered over a pad of diatomaceous earth that was then washed with THF. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography eluted with DCM/MeOH (20/1) to give the titled compound.
Synthesis of Compound 387: 3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-N-(pyrrolidine-3-sulfonyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide




A solution of AC09 (103 mg, 0.15 mmol) in a mixture of THF (8 mL), ethanol (8 mL), acetic acid (1 mL), and aqueous 1 M HCl (1 mL) was degassed with nitrogen. 10% Pd(OH)2 (21 mg, 0.015 mmol) was added, and the reaction mixture was purged with H2. The mixture was stirred for 16 hours at RT under a hydrogen atmosphere (balloon). The reaction mixture was filtered over a pad of diatomaceous earth that was washed with THF. The filtrate and wash were concentrated in vacuo. The residue was partitioned between chloroform (100 mL) and aqueous 1 M NaOH (50 mL). The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with DCM/MeOH (20/1) to give the titled compound.
Synthesis of AC10: 3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-1-(2-methylpyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid




Step 1: ethyl 1-(2-chloro-6-methylpyridin-4-yl)-3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate
To a solution of E168 (64 mg, 0.17 mmol) in dichloromethane (4 mL) at RT was added 2-chloro-6-methylpyridine-4-boronic acid ([1320397-15-6], 43 mg, 0.25 mmol), copper(II) acetate ([142-71-2], 56 mg, 0.31 mmol) and pyridine (66 μL, 0.81 mmol). The reaction mixture was stirred at room temperature under air for 72 hours. The reaction mixture was filtered through a pad of diatomaceous earth. Solids were washed with dichloromethane, and the filtrate was concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel eluted with ethyl acetate/n-heptane (0/1 to 1/0) to give the titled compound.
Step 2: ethyl 3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-1-(2-methylpyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylate
A solution of the compound from the previous step (50 mg, 0.1 mmol) in ethanol (20 mL) was degassed with nitrogen. 10% Pd/C (5 mg, 0.005 mmol) was added, and the reaction mixture was purged with H2. The mixture was stirred for 16 hours at RT under a hydrogen atmosphere (balloon). The reaction mixture was filtered through a pad of diatomaceous earth that was washed with ethanol. The filtrate was concentrated in vacuo to give the titled compound.
Step 3: 3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-1-(2-methylpyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid
The previous compound (50 mg, 0.1 mmol) was dissolved ethanol (5 mL), and aqueous 1 N sodium hydroxide (0.5 mL, 0.5 mmol) was added at RT. The solution was stirred for 16 hours. A phosphate buffer was added (pH 6.2). The solvent was partially removed under reduced pressure, and the resulting mixture was extracted twice with chloroform. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the titled compound.
Synthesis of AC13: 4-[1-(ethoxycarbonyl)piperidin-4-yl]-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid







Step 1: methyl 1-(4-fluorophenyl)-4-(piperidin-4-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylate hydrogen chloride (1/1) HCl salt
E197 (1.7 g, 3.42 mmol) was dissolved into 4 M HCl in dioxane (25.7 mL, 102 mmol), stirred at room temperature for two hours, and then concentrated in vacuo to give the titled compound.
Step 2: methyl 4-[1-(ethoxycarbonyl)piperidin-4-yl]-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylate
Ethyl chloroformate (67 μL, 0.7 mmol) was added dropwise at RT to a stirring solution of the compound from Step 1 (200 mg, 0.42 mmol) and DIPEA (294 μL, 1.7 mmol) in anhydrous DCM (2 mL). The reaction was complete after 2 hours. The reaction solution was diluted with DCM (10 mL) and washed with water (5 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the titled compound.
Step 3: 4-[1-(ethoxycarbonyl)piperidin-4-yl]-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid
The compound from Step 2 (196 mg, 0.42 mmol) was dissolved in THF (5 mL) and aqueous 2 N sodium hydroxide (1.05 mL, 2.1 mmol) was added at RT. The solution was stirred for 20 hours. The resulting mixture was diluted with water (10 mL) and then acidified with aqueous 2 N HCl (1.05 mL). The aqueous phase was extracted twice with DCM. The combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the titled compound.







TABLE XVa







List of intermediate acylsulfonamides













Int.
Structure
Name
SM
method
MW
Mes





AC01




N-(3-chloropropane-1-sulfonyl)-1- (4-fluorophenyl)-4-[4- (methoxymethyl)piperidin-1-yl]-3- (propan-2-yl)-1H-pyrazolo[3,4- b]pyridine-6-carboxamide
A124, 35578-28-0
Y1
566
567


 


AC02




1-{3-[3-(benzyloxy)azetidin-1- yl]phenyl}-N-(methanesulfonyl)-4- [4-(morpholin-4-yl)phenyl]-3- (propan-2-yl)-1H-pyrazolo[3,4- b]pyridine-6-carboxamide
A252, 3144-09-0
Y1
680
681


 


AC03




benzyl 4-({3-cyclobutyl-4-[4- (methoxymethyl)piperidin-1-yl]-1- phenyl-pyrazolo[3,4-b]pyridine-6- carbonyl}sulfamoyl)piperidine-1- carboxylate
A136, S9
Y1
700
701


 


AC04




N-[3-(benzyloxy)propane-1- sulfonyl]-3-cyclobutyl-4-[4- (methoxymethyl)piperidin-1-yl]-1- phenyl-1H-pyrazolo[3,4-b]pyridine- 6-carboxamide
A136, 1408646-99- 0
Y1
631
632


 


AC05




N-[2-(benzyloxy)ethanesulfonyl]-3- cyclobutyl-4-[4- (methoxymethyl)piperidin-1-yl]-1- phenyl-1H-pyrazolo[3,4-b]pyridine- 6-carboxamide
A136, 881407-21-2
Y1
617
618


 


AC06




4-(4-azidophenyl)-N-(3- chloropropane-1-sulfonyl)-1-[3- (dimethylamino)phenyl]-3-(propan- 2-yl)-1H-pyrazolo[3,4-b]pyridine-6- carboxamide
A238, 35578-28-0
Y1
580
581


 


AC07




N-(chloromethanesulfonyl)-3- cyclobutyl-4-[4- (methoxymethyl)piperidin-1-yl]-1- phenyl-1H-pyrazolo[3,4-b]pyridine- 6-carboxamide
A136
Y1
532- 534
533- 535


 


AC08




benzyl [2-({3-cyclobutyl-4-[4- (methoxymethyl)piperidin-1-yl]-1- phenyl-1H-pyrazolo[3,4-b]pyridine- 6- carbonyl}sulfamoyl)ethyl]carbamate
A136, S5
Y1
660
661


 


AC09




benzyl 3-({3-cyclobutyl-4-[4- (methoxymethyl)piperidin-1-yl]-1- phenyl-1H-pyrazolo[3,4-b]pyridine- 6-carbonyl}sulfamoyl)pyrrolidine-1- carboxylate
A136, S7
Y1
686
687


 


AC10




3-cyclobutyl-4-[4- (methoxymethyl)piperidin-1-yl]-1- (2-methylpyridin-4-yl)-1H- pyrazolo[3,4-b]pyridine-6- carboxylic acid
E168
Specific  example
435
436


 


AC11




N-[2-(benzyloxy)ethanesulfonyl]-3- cyclobutyl-1-(4-fluorophenyl)-4-[4- (morpholin-4-yl)piperidin-1-yl]-1H- pyrazolo[3,4-b]pyridine-6- carboxamide
A308
Y1
676
677


 


AC12




N-[2-(benzyloxy)ethanesulfonyl]-3- cyclobutyl-1-(4-fluorophenyl)-4-{4- [2-(piperidin-1-yl)ethyl]piperidin-1- yl}-1H-pyrazolo[3,4-b]pyridine-6- carboxamide
A311
Y1
704
705


 


AC13




4-[1-(ethoxycarbonyl)piperidin-4- yl]-1-(4-fluorophenyl)-3-(propan-2- yl)-1H-pyrazolo[3,4-b]pyridine-6- carboxylic acid
E197
Specific  example
454
455


 


AC14




1-cyclohexyl-4-(4-formylphenyl)-N- (methanesulfonyl)-3-[(propan-2- yl)oxy]-1H-pyrazolo[3,4-b]pyridine- 6-carboxamide
A350
Y1
484
485


 


AC15




tert-butyl 5-(4-{1-cyclohexyl-6- [(methanesulfonyl)carbamoyl]-3- [(propan-2-yl)oxy]-1H- pyrazolo[3,4-b]pyridin-4- yl}benzoyl)hexahydropyrrolo[3,4- c]pyrrole-2(1H)-carboxylate
A351
Y1
694
695


 


AC16




N-[benzyl(methyl)sulfamoyl]-3- cyclobutyl-1-(4-fluorophenyl)-4-[4- (morpholin-4-yl)piperidin-1-yl]-1H- pyrazolo[3,4-b]pyridine-6- carboxamide
A308, 15205-37-5
Y8
662
662


 


AC17




N-[3-(benzyloxy)propane-1- sulfonyl]-3-cyclobutyl-1-(4- fluorophenyl)-4-[4- (methoxymethyl)piperidin-1-yl]-1H- pyrazolo[3,4-b]pyridine-6- carboxamide
A202, 1408646-99- 0
Y1
649
650

















Lengthy table referenced here




US09890158-20180213-T00001


Please refer to the end of the specification for access instructions.














Lengthy table referenced here




US09890158-20180213-T00002


Please refer to the end of the specification for access instructions.






Determination of Biological Activity
Cellular Assays
Measuring CFTR Cell Surface Expression of CFTR-ΔF508 Using PathHunter® U2OS CFTR-ΔF508 cells
The PathHunter® U2OS CFTR-ΔF508 cell assay (DiscoveRx) measures the expression of CFTR-ΔF508 at the plasma membrane. CFTR-ΔF508 has a folding defect leading to absence of protein at the plasma membrane. This assay is used to evaluate the capacity of compounds to increase the expression of CFTR-ΔF508 at the plasma membrane. The CFTR-ΔF508 is tagged with a ProLinkTM peptide which can complement with plasma membrane expressed enzyme acceptor protein (EA-MEM). When both the ProLinkTM and EA-MEM acceptor are in close proximity, i.e. both are located at the plasma membrane; a functional enzyme is formed of which the activity can be measured. The amount of CFTR-ΔF508 that can be rescued to the plasma membrane is correlated with the amount of functional enzyme that can be measured.
There are several ways to measure the capacity of compounds to rescue CFTR-ΔF508 to the plasma membrane; either compounds are evaluated on their own and the impact on plasma membrane levels is measured or compounds are evaluated in combination with a co-corrector, i.e. a compound that rescues CFTR-ΔF508 to the plasma membrane but rescue can be enhanced by addition of compounds due to a complementary mode of action.
Activity of Compounds in Combination with Co-Corrector:
For this purpose, PathHunter® U2OS CFTR-ΔF508 cells (DiscoveRx; custom made were cultured in AssayCompleteTM U2OS Cell Culture medium (DiscoveRx; 92-0018GK3) as per manufacturer's instructions. For compound testing, cells were seeded in white 384-well plates (Greiner; 781080) at five thousand cells/well in 25 μL AssayCompleteTM Cell Plating 5 Reagent (DiscoveRx; 93-0563R5A) and incubated overnight at 37° C., 5% CO2. On day two, 5 L of test compounds diluted in Cell Plating 5 Reagent were added to the cells with a final dimethyl sulfoxide (DMSO) concentration of 0.1%. In order to measure synergy with a co-corrector (3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoic acid), 3 μM of co-corrector was added along with test compounds. All cell plates contained 3 μM of co-corrector or DMSO as positive and negative controls, respectively. Cells were incubated with compounds for twenty to twenty-four hours at 37° C., 5% CO2. On day three, plates were placed at room temperature for thirty minutes and then 15 μL of substrate (PathHunter® Flash Detection Kit, DiscoveRx; 93-0247) was added per well. After one hour of incubation at room temperature in the dark, the luminescence signal was measured on a plate reader (Envision®, Perkin Elmer). Raw data were normalized to percentage activity values using the equation: 100×(Sample−Negative control)/(Positive control−Negative Control).
Activity of Compounds for their Intrinsic Corrector Capacity:
For this purpose PathHunter® U20S CFTR-ΔF508 cells (DiscoveRx; custom made as described above) were cultured in AssayCompleteTM U20S Cell Culture medium (DiscoveRx; 92-0018GK3) as per manufacturer's instructions. For compound testing, cells were seeded in white 384-well plates (Greiner; 781080) at five thousand cells/well in 25 μL AssayCompleteTM Cell Plating 5 Reagent (DiscoveRx; 93-0563R5A) and incubated overnight at 37° C., 5% CO2. On day two, 5 μL of test compounds diluted in Cell Plating 5 Reagent were added to the cells with a final DMSO concentration of 0.1%. All cell plates contained 3 M corrector (3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoic acid) or DMSO as positive and negative controls, respectively. Cells were incubated with compounds for twenty to twenty-four hours at 37° C., 5% CO2. On day three, plates were placed at room temperature for thirty minutes and then 15 L of substrate (PathHunter® Flash Detection Kit, DiscoveRx; 93-0247) was added per well. After one hour of incubation at room temperature in the dark, the luminescence signal was measured on a plate reader (Envision®, Perkin Elmer). Raw data were normalized to percentage activity values using the equation: 100×(Sample−Negative control)/(Positive control−Negative Control).
Activity of Compounds in Presence of Human Serum
To evaluate the impact of plasma protein binding of compounds on their biological activity, the PathHunter® U20S CFTR-ΔF508 assay was run in the presence of 40% human serum (Sigma; H4522). For this purpose PathHunter® U20S CFTR-ΔF508 cells (DiscoveRx; custom made) were cultured in AssayCompleteTM U20S Cell Culture medium (DiscoveRx; 92-0018GK3) as per manufacturer's instructions. For compound testing, cells were seeded in white 384-well plates (Greiner; 781080) at five thousand cells/well in 25 μL AssayCompleteTM Cell Plating 5 Reagent (DiscoveRx; 93-0563R5A) containing 40% human serum and incubated overnight at 37° C., 5% CO2. On day two, 5 μL of test compounds diluted in Cell Plating 5 Reagent were added to the cells with a final DMSO concentration of 0.1%. All cell plates contained 3 μM corrector (4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoic acid) or DMSO as positive and negative controls respectively. Cells were incubated with compounds for twenty to twenty-four hours at 37° C., 5% CO2. On day three, plates were placed at room temperature for thirty minutes, and then 15 μL of substrate (PathHunter® Flash Detection Kit, DiscoveRx; 93-0247) was added per well. After one hour of incubation at room temperature in the dark, the luminescence signal was measured on a plate reader (Envision®, Perkin Elmer). Raw data were normalized to percentage activity values using the equation: 100×(Sample−Negative control)/(Positive control−Negative Control).
Activity of Compounds in Presence of Human Serum
To evaluate the impact of plasma protein binding of compounds on their biological activity, the PathHunter® U20S CFTR-ΔF508 was run in the presence of 40% human serum (Sigma; H4522). For this purpose PathHunter® U20S CFTR-ΔF508 cells (DiscoveRx; custom made) were cultured in AssayCompleteTM U20S Cell Culture medium (DiscoveRx; 92-0018GK3) as per manufacturer's instructions. For compound testing, cells were seeded in white 384-well plates (Greiner; 781080) at five thousand cells/well in 25 μL AssayCompleteTM Cell Plating 5 Reagent (DiscoveRx; 93-0563R5A) and incubated overnight at 37° C., 5% CO2. On day two, the medium was replaced with 25 μL of primary human airway epithelial cell air-liquid interface medium or ALI medium, a 50:50 mixture of DMEM (Dulbecco's Modified Eagle Medium, Invitrogen; 41966-029) and LHC Basal Medium (Invitrogen; 12677-019) with additives as described in Table XVII) and containing 40% human serum. One hour later, 5 μL of test compounds diluted in ALI medium were added to the cells with a final DMSO concentration of 0.1%. All cell plates contained 3 M corrector (4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoic acid) or DMSO as positive and negative controls respectively. Cells were incubated with compounds for twenty to twenty-four hours at 37° C., 5% CO2. On day three, plates were placed at room temperature for thirty minutes and then washed twice with PBS (phosphate buffered saline) followed by the addition of 15 μL of substrate (PathHunter® Flash Detection Kit, DiscoveRx; 93-0247) per well. After one hour of incubation at room temperature in the dark, the luminescence signal was measured on a plate reader (Envision®, Perkin Elmer). Raw data were normalized to percentage activity values using the equation: 100×(Sample−Negative control)/(Positive control−Negative Control).










TABLE XVII






Final





concentration




Ingredient
in medium
Provider
Cat#



















BSA
0.5 
mg/mL
Sigma
A7638


bovine pituitary extract
10 
μg/mL
Sigma
P1476


Insulin
0.87 
μM
Sigma
I9278


transferrin
0.125 
μM
Sigma
T0665


hydrocortisone
0.21 
μM
Sigma
H0396


triiodothyronine
0.01 
μM
Sigma
T6397


Epinephrine
0.01 
μM
Sigma
E4250


epidermal growth factor
5 
ng/mL
Invitrogen
PHG0313










All-trans retinoic acid
  5 × 10−8M
Sigma
R-2625











o-Phosphoethanolamine
0.5 
μM
Sigma
P-0503


ethanolamine
0.5 
μM
Sigma
E0135


zinc sulfate (ZnSO4 · 7H2O)
3.0 
μM
Sigma
Z0251


pen/strep
100 
U/mL
Sigma
15140-






122










ferrous sulfate
1.5 × 10−6M
Sigma
F8048


magnesium chloride hexahydrate
6 × 10−4 
Sigma
M2670


calcium chloride dihydrate
1.1 × 10−4M
Fluka
21097


Trace elements:
—













sodium selenite
30 
nM
Sigma
S5261


manganese chloride tetrahydrate
1 
nM
Sigma
M8054


sodium metasilicate nonahydrate
500 
nM
Sigma
S5904


ammonium molybdate tetrahydrate 
1 
nM
Sigma
M1019


ammonium metavanadate
5 
nM
Sigma
398128


nickel(II)sulfate hexahydrate
1 
nM
Fluka 
72280 





(Sigma)
(N4882)


tin(II) chloride dihydrate
0.5 
nM
Sigma
243523









Measuring CFTR Cell Surface Levels Using HRP-Tagged ΔF508-CFTR Expressing CFBE Cells

The HRP-tagged ΔF508-CFTR cell assay measures the expression of CFTR-ΔF508 at the plasma membrane. CFTR-ΔF508 has a folding defect leading to absence of protein at the plasma membrane. This assay is used to evaluate the capacity of compounds to increase the expression of CFTR-ΔF508 at the plasma membrane. The CFTR-ΔF508 is tagged with HRP (horse radish peroxidase enzyme) within the ECL4 (Extracellular loop 4) of CFTR (Phuan, P.-W. et al. Synergy-based small-molecule screen using a human lung epithelial cell line yields ΔF508-CFTR correctors that augment VX-809 maximal efficacy. Mol. Pharmacol. 86, 42-51 (2014)). When HRP-tagged ΔF508-CFTR is present at the plasma membrane, the HRP enzyme activity can be measured. The amount of CFTR-ΔF508 that can be rescued to the plasma membrane is correlated with the amount of functional enzyme that can be measured.
There are several ways to measure the capacity of compounds to rescue CFTR-ΔF508 to the plasma membrane; either compounds are evaluated on their own and the impact on plasma membrane levels is measured or compounds are evaluated in combination with a co-corrector, i.e. a compound that rescues CFTR-ΔF508 to the plasma membrane but rescue can be enhanced by addition of compounds due to a complementary mode of action.
Activity of Compounds in Combination with Co-Corrector:
For this purpose doxycycline-inducible ΔF508-CFTR-HRP expressing CFBE41o-cells (obtained from Gergely Lukacs, McGill University) were maintained in MEM (Minimum Essential Medium, Gibco; 31095) supplemented with 10% fetal bovine serum (Hyclone; SV30160.03) under puromycin (3 μg/mL) and G418 selection (0.2 mg/mL). For compound testing, cells were seeded at 4000 cells/well in white 384-well plates (Greiner; 781080) in 50 μL of medium containing 0.5 μg/mL doxycycline and incubated for 68 hours at 37° C., 5% CO2. On day four, 10 μL of test compounds diluted in PBS (phosphate buffered saline) were added to the plates at a final DMSO concentration of 0.1%. In order to measure compound synergy with a co-corrector, 3 μM co-corrector (3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoic acid) was added along with test compounds. All compound plates contained negative controls (DMSO) and positive controls (3 M co-corrector). Cell plates were incubated at 33° C., 5% CO2 for 20 hours. On day five, the cells were washed five times with phosphate-buffered saline, and HRP activity was assayed by the addition of 50 μL/well of HRP substrate (SuperSignalTM West Pico Chemiluminescent Substrate, Thermo Scientific; 34080). After incubation for 15 minutes in the dark, the chemiluminescence was measured using a plate reader (EnVision®, Perkin Elmer). Raw data were normalized to percentage activity values using the equation: 100×(Sample−Negative control)/(Positive control−Negative Control).







TABLE XVIII







Illustrative EC50 measured by CFTR cell surface levels using HRP-tagged


ΔF508-CFTR expressing CFBE cells in the presence of a co-corrector.









Compound #
% Activation
EC50 (nM)












1
297.2
1186


2
431.5
1122


4
405.8
297.9


5
362.75
371.75


6
387.1
510.7


7
420.63
554.03


8
441.85
853.8


9
335
505.05


10
606.5
442.65


11
381.33
455.35


12
364.15
713.8


13
341.75
1471


14
335.6
1368


15
346.15
852.15


16
649.9
458.65


17
320
1120


18
217.8
1110


19
304.05
1632.5


20
417.5
545.9


21
440.1
525.3


22
371.55
502.6


23
468.85
573.35


24
380.5
743.95


25
437.17
640.17


26
449.7
1548


27
365.2
714


28
354.45
942.15


29
591.4
823.7


30
580.97
215.37


31
423.27
203.8


32
526
234


33
315.6
470.95


34
462.55
355.9


35
509.7
348.4


36
572.93
245.77


37
457.25
1163.1


38
447.7
581.23


39
378.63
507.77


40
373.43
422.67


41
253.3
1141


42
226.3
378.5


43
627
289.4


44
412.63
276.27


45
438.4
202.94


46
643.27
445.83


47
408.77
1604.3


48
417.8
1152.5


49
338
1996.7


50
300
1075.5


51
420.67
311.5


52
257.85
992.4


53
572.78
647.2


54
593.12
463.62


55
341.65
1047.4


56
336.75
838.1


57
440
657.2


58
352.5
421.8


59
534.8
482.5


60
323.63
351.47


61
415.3
506.2


62
631.2
531.8


63
368.48
285.56


64
362.45
443.65


65
332.05
463.55


66
332.85
6670


67
371.62
241.18


68
456.6
847.1


69
362.03
403.63


70
342.85
409.6


71
447.8
263.55


72
400.9
5611


73
423.35
490.05


74
424.82
357.1


75
387.16
290.54


76
581.37
632.67


77
449.85
831.2


78
520.7
660.5


79
501.6
555


80
457.5
389.5


81
646.44
253.16


82
535.93
383.03


83
567.7
424.5


84
468.2
408.1


85
570.16
232.1


86
489.56
255.04


87
623.62
456.46


88
546.2
412.73


89
609.48
396.26


90
384.95
388.85


91
619.45
890.95


92
367.67
278.4


93
456.5
270.4


94
421.53
341.9


95
611.7
649.15


96
707.5
473.05


97
692.82
277.25


98
360.15
393.3


99
601.15
336.8


100
340.6
3221


101
455.4
409.2


102
458.75
536.55


103
501.03
409.03


104
411.33
344.37


105
457.85
698.9


106
348.1
393.95


107
219.4
3340


108
428.3
509.45


109
571.3
634.1


110
665.7
336.37


111
596.8
377.83


112
472.8
884.2


113
455.63
235.17


114
277.45
951.6


115
389.6
664.65


116
438.37
630.5


117
417.92
200


118
469
280


119
389.93
331.37


120
351.03
347.9


121
368.6
281.8


122
405.9
280.57


123
365.8
238.9


124
447.23
312.03


125
520.33
463.17


126
487.53
322.17


127
449.1
251.85


128
529.57
251.93


129
307.3
790.25


130
496.9
540.3


131
465.1
580.65


132
417.2
881.65


133
417.7
335.87


134
435.8
236.8


135
512.9
373.43


136
428.1
72.26


137
339.7
638.35


138
433.83
235.77


139
335.5
764.83


140
377.9
380.65


141
414.63
221.37


142
376.93
78.407


143
217.8
833.55


144
674.7
242.99


145
271.43
636.17


146
357.55
96.872


147
363.93
99.92


148
448.03
169.85


149
299.95
259.05


150
380.65
318.29


151
387.15
108.87


152
409.9
107.85


153
290.05
130.35


154
447.85
203.45


155
555.45
229.66


156
636.47
360.2


157
542.17
358.74


158
512.45
266.75


159
270.3
483.27


160
490.4
201.8


161
574.1
354.83


162
331.53
304.16


163
342.3
111.91


164
492.45
387.6


165
534.2
884.65


166
408.53
309.97


167
429.4
81.765


168
581.55
409.8


169
519.3
284.36


170
425.6
721.7


171
289.23
312.2


172
462.4
207.07


173
183.2
432.9


174
545
468.45


175
461.1
200.23


176
390.43
208.64


177
263.9
385.45


178
381.73
231.52


179
248.85
405.85


180
290.53
300.17


181
357.93
435.4


182
397.6
258.1


183
498.57
213.78


184
282.7
574.4


185
546.7
145.09


186
381.87
530.53


187
308.87
69.253


188
405.37
159.6


189
409.6
236.27


190
502.4
1240.4


191
317.93
161.26


192
254.6
865.7


193
341.37
589.17


194
427.45
370.65


195
387.47
191.69


196
387.1
231.43


197
390.8
193.94


198
321.57
465.7


199
304.63
316.4


200
318.27
94.83


201
379.9
292.47


202
299.4
254.83


203
224.63
328.1


204
288.6
490.35


205
416.4
856


206
387.03
890.4


207
284.87
174.71


208
419.15
363.65


209
393.6
230.87


210
390.57
173.74


211
288.3
292.9


212
290.43
324.03


213
469.6
336.5


214
250.55
383.85


215
569.35
47.87


216
456.1
299.5


217
418.27
257.13


218
476.9
238.67


219
524.4
230.26


220
389.9
207.87


221
492.2
77.24


222
247.3
1788.2


223
438.2
371


224
453.1
482


225
427.95
578.55


226
392.95
386.1


227
378.2
307.3


228
395.1
334.9


229
418.65
366.1


230
440.1
179.98


231
329.9
518.2


232
199.75
1726.5


233
206.57
1925.3


234
128.3
>10000


235
257.55
2485


236
497.5
93.19


237
264.05
222.18


238
347.55
218.6


239
431.55
1235.2


240
312.8
138.7


241
488.15
82.165


242
459.15
202.77


243
204.1
3330


244
290.6
413.5


245
460
693.6


246
331.65
77.25


247
281.7
220.67


248
450.6
221.44


249
468.15
231.26


250
440.4
372


251
488.7
367


257
310.75
1691


253
454.4
250.85


254
312.1
370


255
365.8
3330


256
508.63
147.3


257
451.25
74.3


258
127.1
>10000


260
664.07
129.88


261
129.3
>10000


262
420.17
523.02


263
475.45
403.78


264
478.6
3330


265
427.8
2138


266
328.87
230.63


267
433
57.095


268
122.05
>10000


269
275.45
97.25


270
327.9
730.83


271
260.47
1016.5


272
451.2
43.33


273
344.05
111.1


274
300
398.1


275
269.85
138


276
417.25
42.905


277
355.4
127.1


278
388.5
88.315


279
530.6
227.4


280
323.37
1010.2


281
398.47
242.33


282
379.95
89.015


283
326.85
265.5


284
348.7
219.8


285
327.57
246


286
500.55
158.6


287
450.9
128.29


288
566.4
74.34


289
366.4
3330


290
382.2
535.7


291
420.07
590.9


292
422.55
564.7


293
317.1
479.7


294
548.45
22.065


295
298.07
697.2


296
329.13
167.8


297
423.43
77.2


298
481.2
81.025


299
267.2
2514.5


300
266.55
109.26


301
376.6
1136.4


302
401.45
1799.6


303
339.95
834.25


304
507
56.145


305
267
2443


306
321.1
82.395


307
299.25
1278.8


308
328.85
2492.5


309
303.6
224.05


310
251.5
923.65


311
241.35
1060.6


312
291.5
1882.5


313
319.75
1749


314
375.8
693.1


315
315.5
101.55


316
555.55
24.4


317
450.35
48.825


318
359.5
184.25


319
232
979.57


320
590.6
82.663


321
314.37
496.53


322
342.75
61.415


323
292.85
372.05


324
259.7
1635.4


325
309.8
152.6


326
325.3
729.7


327
433.9
99.9


328
554.2
185.7


329
318.4
777.1


330
285.4
124.3


331
546.05
38.185


332
448.25
624.3


336
232.42
282.15


337
532.3
30.55


338
344.25
945.55


339
295.5
402.1


340
319.2
785.8


341
165.4
3330


342
336.5
207.1


343
356.9
566.3


344
374.5
1061


345
301.1
222.8


346
375.1
253.45


347
301.15
54.26


348
468.65
723.5


349
327.9
424.45


350
274.6
286.95


351
232.5
81.07


352
158.4
2778


353
193.45
346.44


354
351
232.2


355
278.4
377.1


356
372
48.27


357
229.8
129.5


358
242.33
89.854


359
236.25
298.9


360
182.8
100.72


361
204.1
181.2


362
195.75
413.8


363
415.8
116.2


364
575
553


365
469.95
271.05


366
443.7
82.67


367
526.17
81.56


368
350.23
361


369
444
105.88


370
343.2
691.05


371
271.9
1926.5


377
615.7
2560


373
580.5
85.76


374
426.05
195.67


375
546.75
241.45


376
496.8
51.61


377
485.55
102.74


378
318.6
657.55


379
440.55
61.09


380
309.17
127.16


381
432.09
155.99


382
500.01
158.29


383
412.20
94.26


384
391.35
1443


385
393.53
64


386
385.05
684.75


387
168.9
160.7


388
364.5
195.93


389
305.1
297.3


390
350.17
139.8


391
441.15
85.535


392
421.4
138.66


393
533.65
20.77


394
366.87
47.877


395
327.95
126.69


396
385.8
55.037


397
381.8
48.963


398
324.03
73.623


399
388.77
44.157


400
365.43
156.83


401
595.1
61.98


402
471.42
116.35


403
507.35
25.628


404
370
125.8


405
326.9
101.86


406
311.35
181.65


407
494.15
124.02


408
466.58
199.45


409
481.1
108.14


410
529.58
82.442


411
505
478.2


412
436.4
200.6


413
455.9
90.59


414
508.3
158.6


415
598
69.31


416
458.65
64.97


417
539.75
91.905


418
512.9
220.8


419
505.65
277.1


420
486.65
209.2


421
512.9
124.75


422
434.33
204.27


423
376.85
108.84


424
453.88
92.203


425
462.85
166.45


426
385.3
82.03


427
419.5
162.5


428
434.7
77.27


429
422.8
205.15


430
383.7
89.87


431
568.8
47.003


432
514.83
65.943


433
563.8
49.01


434
470.37
59.51


435
474.8
82.825


436
568.6
71.07


437
563.64
155.81


438
541.5
380.5


439
374.6
381


440
543.55
55.44


441
393.27
196.47


442
342
1110


443
332.5
183.9


444
361.3
235.1


445
671.25
59.11


446
669.9
77.435


447
543.1
64.69


448
431.1
180.75


AC07
466.9
76.57


450
443.25
246.25


451
391
2102


452
478.25
941.8


453
385.1
319


454
430.2
639.4


456
457.7
93.273


457
508
139.41


458
282.8
920.4


459
388.87
96.053


460
306.75
505.05


461
364.1
177.2


462
495.1
106.85


463
490.6
194.5


464
423.3
170.38


465
293.15
360.35


466
522.47
64.097


467
229.15
270.35


468
443.05
524.2


469
469.4
125.4


470
485.5
114.8


471
446.07
122.4


472
399.79
249.47


473
370.7
43.935


474
390.2
524.45


475
289.95
112.32


476
355.65
151


477
536.7
34.725


478
476.7
126.64


479
524.1
108.95


480
545.77
87.11


481
285.65
154.25


482
436.4
61.63


483
438.2
56.15


484
485.6
142.1


485
399.1
90.217


486
569
180.5


487
404.63
68.97


488
488.15
682.55


489
280
241.2


490
303.9
692.6


491
490.9
487.8


492
483.4
43.91


493
480.78
94.585


494
551.8
37.085


495
469.08
66.152


496
374.65
242.9


497
378.25
287.65


498
456.3
95.12


499
439.6
71.165


500
330.05
84.215


501
403.55
124.3


502
383.8
176.9


503
433.2
404.7


504
404.8
210.05


505
389
54.11


506
308.95
941.25


507
580.4
95.4


508
448.8
90.31


509
527.9
118.4


510
428.8
170.9


511
432.95
78.94


512
415.25
65.265


513
476.3
66.74


514
540.3
97.07


515
479.2
52.88


516
545.3
56.56


517
520.08
75.79


518
189.55
3125.5


519
252.3
1023.3


520
207.1
923.7


521
217.3
711.5


522
525.66
79.788


523
451.33
100.04


524
398.75
307.55


525
460.3
73.968


526
472.58
106.56


527
500
53.775


528
357.9
834.45


529
444.13
22.557


530
464.6
22.955


531
349.65
63.465


532
342.83
472.67


533
322.45
220.95


534
289.35
344.1


535
670.35
1251.9


536
341.15
280.1


537
417.1
50.845


538
427.95
357.55


539
429.3
38.63


540
443.3
102.59


541
457.2
114.95


542
320.3
216.1


543
336.1
139.25


544
344.9
1996.4


545
318.7
1905.4


546
335.3
181.9


547
372.95
348.5


548
556.9
553.5


549
476.35
180.4


550
605.45
173.15


551
403.1
382.3


552
364.2
130.43


553
494.3
233.25


554
481
56.86


555
432.55
104.12


556
595.8
136.2


557
474.4
116.35


558
571.35
106.46


559
291.03
154.3


560
544.45
66.1


561
509.4
43.023


562
589.55
77.645


563
542.9
111.13


564
587.4
40.75


565
637.53
69.86


566
708.8
400.42


567
539.8
56.343


568
461
46.295


569
436.13
88.907


570
412.9
208.3


571
487.9
77.77


572
412.9
225.1


573
467.57
58.533


574
283.3
541.9


575
361.3
87.8


576
443.5
54.673


577
379.3
104.7


578
462.3
107.6


579
420.5
318.8


580
387.45
52.425


581
191.3
760.8


582
245.15
271.05


583
480.15
47.595


584
337.55
272.35


585
509.7
247.75


586
618.65
37.12


587
504.6
398.2


588
571.2
29


589
422.95
148


590
487.9
31.395


591
384
1592


592
518.55
56.8


593
366.7
193.7


594
308.05
181.45


595
231.9
1430


596
304.8
1908


597
433.93
110.63


598
153.9
10000


599
285.2
269.7


600
326.1
1618


601
273.9
625


602
359.1
581.4


603
344.65
156.3


604
268.3
300


605
395.8
723


606
513.7
468.6


607
484.3
667.1


608
365.7
54.765


609
414.2
108.91


610
375.5
118.72


611
236.7
2620


612
320.8
3330


613
152.9
10000


614
381.35
170.65


615
450.85
130


616
341.15
294.35


617
324.25
978.45


618
295.9
702.35


619
277.25
374.7


621
348.55
76.95


622
251.25
308.6


623
424.77
55.623


624
274.15
549.2


625
353.87
125.87


626
418.4
111.06


627
348.57
24.793


628
477.32
131.66


629
546.75
266.92


630
593.42
374.58


631
352.63
2986.2


632
466.83
153.9


633
400.44
206.9


634
439.44
78.79


635
449.25
73.852


636
388.85
434.18


637
413.4
971.25


638
606.08
95.005


639
464.55
74.532


640
416.48
107.31


641
443.12
46.265


642
430.9
97.285


643
445.25
496.82


644
529.95
160.16


645
384.37
244.21


646
447.9
259.12


647
337.07
112.2


648
288.85
110.15


649
231.7
152.35


650
592.45
96.375


651
532.4
127.6


652
499.65
24.855


654
347.6
114.46


656
289.68
71.475


657
270.75
196.82


658
270.6
148.53


659
290.95
130.45


660
172.1
235.5


661
227.45
135.34


662
346.65
104.39


663
206.5
102.86


664
230.48
172.5


665
271.8
100.86


666
266.6
121.58


667
225.5
85.485


668
307.4
257.2


669
394
244.4


670
477.6
191.3


671
346.1
107


672
422.4
127.3









Activity of Compounds for their Intrinsic Corrector Capacity:

For this purpose doxycycline-inducible ΔF508-CFTR-HRP expressing CFBE41o-cells (obtained from Gergely Lukacs, McGill University) were maintained in MEM (Gibco; 31095) supplemented with 10% fetal bovine serum (Hyclone; SV30160.03) under puromycin (3 μg/mL) and G418 selection (0.2 mg/mL). For compound testing, cells were seeded at 4000 cells/well in white 384-well plates (Greiner; 781080) in 50 μL medium containing 0.5 μg/mL doxycycline and incubated for 68 hours at 37° C., 5% CO2. On day four, 10 μL test compounds diluted in PBS were added to the plates at a final DMSO concentration of 0.1%. All compound plates contained negative controls (DMSO) and positive controls (3 μM corrector, 3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoic acid). Cell plates were incubated at 33° C., 5% CO2 for 20 hours. On day five, the cells were washed five times with phosphate-buffered saline, and HRP activity was assayed by the addition of 50 μL/well of HRP substrate (SuperSignalTM West Pico Chemiluminescent Substrate, Thermo Scientific; 34080). After incubation for 15 minutes in the dark, chemiluminescence was measured using a plate reader (EnVision®, Perkin Elmer). Raw data were normalized to percentage activity values using the equation: 100×(Sample−Negative control)/(Positive control−Negative Control).







TABLE XIX







Illustrative EC50 measured by CFTR cell surface levels


using HRP-tagged ΔF508-CFTR expressing CFBE cells.









Compound #
% Activation
EC50 (nM)












1
138.85
1628.9


2
226.75
1867


3
53.08
3340


4
246.7
838.35


5
184.6
476.6


6
232.1
808.3


7
245
636


8
270.6
899.55


9
143.05
785.9


10
418.25
572.5


11
164.7
556.52


12
161.15
1072.5


13
153.85
2361


14
148.9
1429.5


15
151.65
1192.5


16
469.75
543.05


17
140.75
1225.5


18
64.675
2267


19
140.85
2652.5


20
210.3
669.15


21
264.25
685.3


22
161.5
731.65


23
287.3
883.5


24
193.75
887.75


25
247.23
996.8


26
202.25
1847.5


27
145.5
1219


28
149.7
1218


29
328.4
645.05


30
369.93
436.27


31
203.4
318.2


32
277.65
372.25


33
109
2578.5


34
292.95
610.75


35
265.23
542.1


36
384.57
415.9


37
222.85
1662


38
182
849.97


39
143.4
838.2


40
147.1
450.97


41
52.497
816.53


42
45.225
2123


43
379.67
299.47


44
203.87
404.4


45
210.97
326.73


46
457.3
706.07


47
169.73
1862


48
160.9
1195.9


49
115.3
2566.7


50
109.8
1683.5


51
172.4
456.57


52
75.755
1153


53
376.8
671.1


54
386.92
779.92


55
126.75
1220.2


56
122.1
1177


57
219.65
1024.5


58
196.2
756.33


59
317.3
777.47


60
160.43
394.4


61
184.35
1003


62
350.85
595.75


63
179.68
548.28


64
152.75
935.35


65
162.33
1532.5


66
142.65
1861.4


67
181.96
361.86


68
253.3
1079


69
182.08
631.68


70
167.8
621.35


71
260.66
350


72
232.5
2226.5


73
254.1
657.45


74
253.38
549.12


75
225.82
489.92


76
430.87
528.07


77
296.45
639


78
333.2
1878.3


79
280.9
1227


80
258.38
436.18


81
495.8
384.52


82
366.27
472.07


83
391.5
547.1


84
311.7
659.8


85
426.04
420.84


86
329.92
637.3


87
422.84
408.78


88
389.73
474.4


89
422.78
645.7


90
163.75
485.6


91
388.15
381.7


92
175.77
552.8


93
224.23
501.2


94
193.5
614.33


95
355.6
837.85


96
406.6
366.9


97
444.85
399.2


98
154
555.55


99
414.8
409.65


100
113
2475


101
254.85
838.65


102
233.9
897.2


103
263.8
535.87


104
239.6
496.9


105
258.1
908.4


106
162.75
525.9


107
64.54
3340


108
218.05
560.55


109
381.05
612.85


110
451.8
358.13


111
411.63
444.3


112
254.85
699.5


113
262.33
464.4


114
130.85
1136


115
216.05
1050


116
295.57
957.23


117
281.88
332.78


118
289.93
397.63


119
188.53
519.5


120
169.2
553.7


121
159.13
652.53


122
184.53
469.67


123
153.8
428.27


124
288.1
544.77


125
369.87
988.13


126
309.17
597.03


127
301.45
517.9


128
357.47
515.83


129
187.5
1326.5


130
318.25
541.35


131
314.35
429.85


132
244
1270.5


133
222.33
412.87


134
229.87
465.2


135
299.63
695.8


136
262.38
154.65


137
131.8
1173.2


138
252.9
333.73


139
163.83
806.07


140
210.3
733.5


141
233.07
287.2


142
203.17
254.9


143
107.15
1110


144
531.6
416.52


145
112.03
1039.4


146
201.23
356.08


147
176.47
358.63


148
273.33
547.73


149
122.3
385.75


150
220.98
576.45


151
228.95
346.65


152
242.35
357.15


153
146.7
354.95


154
275.65
532.9


155
439.5
454.35


156
411
438.63


157
327.8
460.03


158
359.1
622


159
103.02
661.2


160
285.57
309.47


161
406.4
729.53


162
169
445.43


163
175.4
441.8


164
295.25
594.45


165
373.95
1781


166
235.2
439.43


167
260.6
313.35


168
399.2
338.2


169
344.25
426.22


170
213.5
974.85


171
143.4
787.07


172
280.03
329.77


173
51.395
412.4


174
347.9
753.6


175
270.5
337.5


176
190.4
337.3


177
99.405
829.6


178
202.8
346.9


179
89.165
878.85


180
129.5
570.07


181
137.73
397.87


182
207.57
501.43


183
302
389.5


184
95.405
719.25


185
331.6
241.45


186
209.57
616.13


187
160
223.43


188
214.93
274.5


189
236.2
420.6


190
284.8
966.55


191
161.23
305.6


192
81.49
1135


193
175.23
1067.5


194
213.75
744.5


195
225.2
369.7


196
188.47
339.43


197
220.2
397


198
135.73
632.97


199
142.6
481.47


200
163.43
315.7


201
200.8
402.17


202
147.23
595.43


203
82.59
1015.5


204
117.6
977.95


205
208.5
955.55


206
169.03
1396.1


207
141.93
339.73


208
190.55
402.45


209
247.6
380.97


210
205.57
285.6


211
114.4
608.15


212
114.63
620.9


213
267.5
546.25


214
103.6
1010.8


215
374.57
274.4


216
275.67
765.67


217
246.77
458.47


218
268.37
390.4


219
381.1
764.1


220
202.5
347.9


221
322.15
420.05


222
65.685
1423.2


223
258.95
469.5


224
228.8
544.2


225
215.35
456.25


226
206.7
445.05


227
216.8
448.6


228
217.9
489.9


229
174.2
414.1


230
243.75
406.1


231
162.9
939.25


232
71.64
1678


233
58.34
2438


234
17.89
>10000


235
102.76
3271


236
309.83
316.47


237
120
453.2


238
159.83
600.57


239
184.6
999.25


240
176.67
376.63


241
261.93
366.43


242
242.1
282.83


243
78.11
3340


244
182.7
381.2


245
228
495.1


246
112.1
371


247
126.8
460


248
234.6
371


249
187.6
371


250
232.7
514


251
273.3
634


252
115.2
396.5


253
174.6
675.6


254
117.5
399.8


255
122.3
1881


256
331.85
220.65


257
272.4
370


258
8.829
>10000


260
473.35
1868.6


261
26.85
>10000


262
232.07
597.87


263
260.1
444.83


264
242.5
969.2


265
240.8
3330


266
161.5
332


267
274.8
171.6


268
5.213
>10000


269
120.6
246.4


270
161.5
1493


271
63.905
1952


272
268.2
96.55


273
182.4
562.4


274
159.05
842.5


275
138.8
467.7


276
356.7
779.3


277
155.4
251.1


278
233.7
119.5


279
308.4
533.7


280
121.9
1007


281
230.15
456.5


282
127.8
129.3


283
141.2
477


284
154.4
275.7


285
125.5
293.8


286
264
326.8


287
204.9
183.2


290
200.4
617.4


291
219.5
3330


292
217.9
1057


293
113.3
622.2


294
319.6
62.24


295
129.6
1052


296
154.7
396.5


297
193.9
99.18


298
312.9
282.1


299
81.41
3330


300
119.9
309.4


303
149.9
3330


304
308.2
202.9


306
146.7
157.7


307
172.7
3330


309
149
444.3


310
66.84
691.9


315
154.87
218.03


316
380.5
182.8


317
269.6
93.52


318
183.45
411.25


319
34.315
297.7


320
376.35
309.35


322
158.25
128.05


323
144.6
1366


325
151.4
334.8


326
167.1
2384.5


327
239.4
145.2


328
380.5
2186


329
163.85
158.2


330
133.1
213.45


331
347.15
136.25


333
180
82.765


334
121.75
167.4


335
171.65
149.85


336
107.2
419.9


337
404.9
133.58


339
142.05
1401


340
138.95
1392


346
195.8
308.2


347
131.4
263


348
293.6
5969.5


349
161.7
512.3


350
104.21
357.15


351
50.87
73.45


352
27.44
5000


353
56.22
87.86


354
113.7
122.9


355
102.4
160.5


356
188.25
105.3


357
72.83
115.2


365
313
1670


366
264
297.9


367
364.5
311.4


368
185
1359


369
292.7
100.6


370
172.2
1490


371
121.3
2744


373
368.2
72.97


374
240.7
254.3


375
321.6
570.9


376
355.7
117.4


377
261.3
129


378
160
1327


379
268.45
141.1


380
131.7
279.3


381
247.15
424.06


382
305.9
260.6


383
202.9
149.8


384
228
2862


385
227.5
120.95


386
237.85
2116


387
60.58
462


388
192.8
217.9


389
165
556.1


390
188.2
176.9


391
247.7
77.1


392
240.05
150.45


393
423.6
51.37


394
194.35
99.53


395
209.2
473.8


396
222.9
121.35


397
234.5
154.55


398
173.7
181.5


399
237.5
72.075


400
180.65
163.05


401
400.8
104.1


402
303.5
312.28


403
389.2
30.18


404
181.2
185.6


405
160.8
190.7


406
125.95
240.8


407
331.45
496.9


408
272.74
689.62


409
245.4
154.9


410
337.42
212.87


415
365.4
165.4


416
288
141.9


417
307.45
189.7


418
321.3
320.9


419
293
448.1


420
283.1
472


421
308
250.1


422
222.8
318.5


423
175.55
140.1


424
249.25
244.25


425
280.2
277.1


426
143.7
301.6


429
252.1
378


430
170.05
231.3


431
344.95
109.3


432
243.6
118.5


433
361.5
96.46


434
245.2
57.74


435
269.9
135.9


436
393.3
344


437
353.8
257


438
337
391.8


439
166.8
550


440
334.8
129


441
196.1
350


442
146.8
307.3


444
162.5
344.7


445
393.1
110.7


447
330.9
243.5


448
258.2
476.9


AC07
268.5
139.5


450
253.5
617.5


451
184.1
1698


452
239.8
408.4


453
149.3
403


454
168.1
1670


456
268.4
157.7


457
272.2
128.5


458
124.4
794.4


459
225.65
148.95


460
125.8
595.6


461
212.3
209.4


462
317.4
775.5


463
263.9
419.1


464
277.5
306.3


465
131.6
312.8


466
318.7
175.8


469
253.8
203.9


470
275.4
231.1


471
240.2
230.2


472
210.57
680.74


473
166.3
70.76


474
194.5
580.5


475
140.1
178.8


476
134.2
215


477
341.4
117


478
295.4
2639


479
305.7
196.6


480
322.45
135.7


481
114.2
278.1


482
214.1
88.17


483
212.7
84.88


484
216.9
124.3


485
218.55
155.15


486
332.5
467.3


487
203.53
174.87


488
246.55
655.45


489
99.6
141.5


490
139.7
1546


491
204.5
248.3


492
311
79.93


493
275.2
174.6


494
315.4
109.8


495
242.05
217.1


496
199.9
281.8


497
195.7
410.4


498
288.1
144.3


499
287.5
186.4


500
137.5
173.5


501
188.7
210.7


502
214.2
345.4


503
203.4
418.8


504
206.4
300.8


505
187.5
92.57


506
144.1
3330


507
309.4
136.8


508
217.5
182.2


509
333.2
326.6


510
234.9
297.6


511
248.55
88.31


512
222.27
120.97


513
278.5
100.5


514
301.4
149.8


515
287.1
179.2


516
322.7
120.2


517
320.5
183.95


518
35.86
10000


519
114.4
3330


520
60
1056


521
31.93
10000


522
317.9
114.21


523
236.53
123.6


524
209.35
525


525
274.75
137.75


526
269.23
152.72


527
295.95
79.095


528
185.8
859.1


529
278.55
60.605


530
323.1
54.43


531
182.8
234.05


532
151.95
521.25


533
156.3
221.85


534
105
240.7


535
385.8
389


536
125.1
224.8


537
214.5
112.2


538
228.9
2073


539
234.5
71.71


540
248.8
123.3


541
231.7
444.2


542
153.2
266.8


543
115.7
238.2


544
135.3
3330


545
112.7
3330


546
138.05
325.2


548
307.2
654.3


549
276.9
232.9


550
347
361


551
197.8
763.15


553
293
1732


554
269.45
108.15


555
235.5
358.77


556
386
64.67


557
248.5
252


558
399.1
531.6


560
260.4
96.34


561
311.6
107.08


562
341.3
70.505


563
298.9
198.3


564
361.35
117.81


565
373.15
181.8


566
365.1
112.3


567
312.2
139.4


568
240.65
77.465


569
220.77
112.18


570
235.8
496.2


571
268.15
128.75


572
237.55
295.1


573
270.53
104.32


574
129.9
2756


575
202.65
147.4


576
257.15
139.41


577
187.15
256.6


578
309.25
152.15


579
205
375.87


580
201.52
130.88


581
33.38
370


582
75.38
370


583
269.7
178.2


584
164.3
176.7


585
316.6
1242


586
331.67
52.367


587
277.1
234.6


588
366.8
125.95


589
193.6
199.6


590
290.3
86.7


591
189.1
795.1


592
300.8
182.6


593
157.8
189.7


594
135.7
518.85


595
58.87
1519


596
104.3
1381


597
214.3
130.2


598
28.03
10000


599
88.94
331.3


600
126.5
1213


601
112
2177


602
133.6
1177


603
136.2
282.7


604
86.51
490.4


605
207.5
317.5


606
283.8
973


607
272.6
342


608
194.67
103.52


609
202.53
249.1


610
182.13
185.8


611
77.39
3330


612
108.7
875.8


613
30.09
10000


614
172
211.3


615
255.3
482.5


616
144.05
348.1


617
137.1
871.25


618
112.8
420.6


619
102.8
680.25


621
160.45
172.9


622
89.445
568.4


623
238.53
112.73


624
100.59
1203.1


625
182.2
222.97


626
206.6
150.83


627
162.47
82.293


628
283.25
425.38


629
337.34
517.05


630
339.64
738.66


631
122.53
3336.7


632
252.75
304.4


633
180.46
345.2


634
227.46
199.84


635
216.38
154.84


636
182.7
572.78


637
191.88
2502.2


638
398.98
241.05


639
238.35
131.92


640
203.62
174.7


641
205.35
74.852


642
222
234.88


643
181.65
505.98


644
266.9
253.35


645
194.33
331.1


646
236.13
400.12


647
164.47
215.73


648
109.65
315.7


649
69.12
370


650
385.4
115.06


651
317.85
205.75


652
289.03
84.117


654
73.925
5075.4


656
102.63
99.61


657
98
281.48


658
99.025
252.5


659
96.44
141.95


660
34.92
932


661
67.125
154.65


662
134.35
123.75


663
57.9
234.35


664
70.082
277.62


665
101.9
259.35


666
99.775
255.6


667
75.435
208.1


668
89.495
384.5


669
334.9
211.35


670
399.2
276.75


671
252.95
273.5


672
362.9
330.9


673
423.5
288.5


675
398.1
315.6


674
389.5
155.9


676
251.1
251.3


677
458.5
170.7


678
345.1
220.9


679
476.9
131.7


680
351.2
339.1


681
366.2
172


682
260.8
297.2


683
354.9
252.9


684
356.9
114.6


685
144.3
769.9









YFP-Halide Influx Assay for the CFTR-ΔF508 Mutation

The YFP halide influx assay measures the functionality of the Cystic Fibrosis Transmembrane Conductance regulator (CFTR) channels in the cystic fibrosis bronchial epithelium cell line CFBE41o-. The fluorescence of the yellow fluorescent protein (YFP) variant YFP H148Q, I152L or variant YFP H148Q, I152L & F47L is substantially quenched by iodine, a halide that is efficiently transported by CFTR. The assay is thus used to evaluate the effect of corrector compounds on CFTR channel function by measuring the extent of YFP signal quenching. (Galietta, L. J. V., Haggie, P. M., Verkman, A. S., 2001. Green fluorescent protein-based halide indicators with improved chloride and iodide affinities. FEBS Lett. 499, 220-224. doi: 10.1016/S0014-5793(01)02561-3; Nagai, T., Ibata, K., Park, E. S., Kubota, M., Mikoshiba, K., Miyawaki, A., 2002. A variant of yellow fluorescent protein with fast and efficient maturation for cell-biological applications. Nat. Biotechnol. 20, 87-90. doi: 10.1038/nbt0102-87). For this purpose, CFBE41o-cells were seeded in 96-well plates (6000 CFBE cells/well). One day after seeding, the CFBE cells were transduced with adenoviral vectors that direct the expression of the CFTR ΔF508 mutant and of the YFP reporter. Cells were treated with test compounds for 24 hours at 37° C. to allow trafficking of corrected CFTR to the membrane. The next day the CFTR channels were activated by treatment with the cAMP inducer forskolin (10.67 μM) and potentiator, N-(3-carbamoyl-5,5,7,7-tetramethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl)-1H-pyrazole-5-carboxamide (0.5 μM), in 1×D-PBS (from Gibco, Cat n#14090-091) for 20 minutes prior to addition of an I− solution (137 mM NaI, 2.7 mM KI, 1.76 mM KH2PO4, 10.1 mM Na2HPO4, 5 mM glucose). The potentiator, 3-amino-N-[(2S)-2-hydroxypropyl]-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridine-2-carboxamide, was used in place of N-(3-carbamoyl-5,5,7,7-tetramethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl)-1H-pyrazole-5-carboxamide in some assays. The F induced quenching of fluorescence is recorded immediately after injection of I for 7 seconds. The capacity of a compound to increase number of channels, and therefore overall halide influx is directly correlated with the decrease in fluorescence, and is expressed as (1−(fluorescence after 7 seconds (F)/fluorescence before injection (F0))) and an EC50 can be derived from a (1−F/F0) vs compound concentration plot.
TECC Assay
Primary Bronchial Epithelial Cells Protocol
The TECC (Tranepithelial Clamp Circuit, EP-design) assay measures the functionality of the cystic fibrosis Transmembrane Conductance regulator (CFTR) by measuring the short circuit current (ISC) generated over the basolateral and apical membrane of lung epithelial cells. In TECC the transepithelial potential PD and transepithelial resistance (Rt) are measured in an open circuit and transformed to Ieq using Ohm's law. 24 Wells can be measured simultaneously allowing a higher throughput compared to Ussing chambers.
For this purpose, bronchial epithelial cells isolated from CF patients homozygous for the CFTR ΔF508 mutation (hAEC-CF, Epithelix, Geneva, Switzerland; McGill University, Montreal, Qc; Asterand, Detroit, Mich.; University of North Carolina, Chapel Hill, N.C.) are plated on type IV collagen-coated Transwell® supports (Costar). Human airway epithelia are generated by provision of an air-liquid interface for 21 days to form well-differentiated polarized cultures that resemble in vivo pseudo-stratified ciliated epithelium (Fulcher, M. L., Gabriel, S., Burns, K. A., Yankaskas, J. R., Randell, S. H., 2005. Well-differentiated human airway epithelial cell cultures. Methods Mol. Med. 107, 183-206). The differentiated cells are treated with test corrector compound(s) (corrector compound(s) (corrector alone or in combination with co-corrector, 4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoic acid (“acute”) or test corrector compounds, co-corrector and potentiator, N-(3-carbamoyl-5,5,7,7-tetramethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl)-1H-pyrazole-5-carboxamide (“chronic”) for 24 hours basolaterally to allow sufficient expression of properly folded CFTR protein on the membrane. All compound plates contained negative controls (DMSO) and positive controls (0.15 μM, 4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic acid).
For electrophysiological recording of the “acute” experiments, the human airway epithelia are mounted in the TECC heating plate and kept at 37° C. The epithelia are bathed in a NaCl-Ringer solution (120 mM NaCl, 25 mM NaHCO3, 1.2 mM CaCl2, 1.2 mM MgCl2, 0.8 mM KH2PO4, 0.8 mM K2HPO4, pH 7.4, 5 mM glucose) on both the basolateral and apical sides. Apical amiloride is used to inhibit the endogenous epithelial sodium channel (ENaC) currents while forskolin is applied on both apical and basolateral side to stimulate CFTR. CFTR activity is measured by addition of forskolin followed by addition of a potentiator, N-(3-carbamoyl-5,5,7,7-tetramethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl)-1H-pyrazole-5-carboxamide, on both sides. The potentiator, 3-amino-N-[(2S)-2-hydroxypropyl]-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridine-2-carboxamide, was used in place of N-(3-carbamoyl-5,5,7,7-tetramethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl)-1H-pyrazole-5-carboxamide in some assays. Measurements are done during a 20 minute timeframe with recordings every 2 minutes. The increase in Ieq is used as a measure for the increased CFTR activity, EC50 values can be generated by measuring impact of different concentrations of compound on Ieq on primary cells, for this purpose each transwell is treated with a different compound concentration for 24 hours. Inhibitor-172, an inhibitor specific for CFTR, is used to test the specificity of the tested compounds. Raw data were normalized to percentage activity values using the equation: 100×(Sample−Negative control)/(Positive control−Negative Control).







TABLE XX







Illustrative acute TECC assay response with


and without the presence of a co-corrector.











% Activity at
% Activity at
% Activity at 3 μM with


Compound #
3 μM (Ieq*)
10 μM (Ieq*)
co-corrector (Ieq*)













10
591.84




11
351


13
74.32
174.53


104


102.36





*Ieq refers to calculations based on the maximum current.






For electrophysiological recording of the “chronic” experiments, the human airway epithelia are mounted in the TECC heating plate for electrophysiological measurement and kept at 37° C. The epithelia are bathed in a NaCl-Ringer solution (120 mM NaCl, 25 mM NaHCO3, 1.2 mM CaCl2, 1.2 mM MgCl2, 0.8 mM KH2PO4, 0.8 mM K2HPO4, pH 7.4, 5 mM glucose) on both the basolateral and apical sides. Test compounds (corrector, co-corrector, 4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic acid, and potentiator, N-(3-carbamoyl-5,5,7,7-tetramethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl)-1H-pyrazole-5-carboxamide), are re-added to the recording solution prior to measurement. The potentiator, 3-amino-N-[(2S)-2-hydroxypropyl]-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridine-2-carboxamide (1.5 M), was used in place of N-(3-carbamoyl-5,5,7,7-tetramethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl)-1H-pyrazole-5-carboxamide in some assays (for Compound numbers >370). Apical amiloride is used to inhibit the endogenous ENaC currents while forskolin is applied on both apical and basolateral side to stimulate CFTR. Measurements are done during a 20 minute timeframe with recordings every 2 minutes. The increase in Ieq is used as a measure for the increased CFTR activity, EC50 values can be generated by measuring impact of different concentrations of compound on Ieq on primary cells, for this purpose each transwell is treated with a different compound concentration. Inhibitor-172, an inhibitor specific for CFTR, is used to test the specificity of the tested compounds. Raw data were normalized to percentage activity values using the equation: 100×(Sample−Negative control)/(Positive control−Negative Control).







TABLE XXI







Illustrative chronic TECC assay response.















% Activity
% Activity




% Activity
EC50
at
at



Compound
at 1 μM
(nM)
1 μM
3 μM
EC50 (nM)


#
(Ieq*)
(Ieq*)
(AUC**)
(AUC**)
(AUC**)















30
450
<30





34
270
<30





63
325
40





71
270
19.5





74
240
<30





75
316
30





80
250
19.3





85
120
>1000





86
210
30





87
150
<30





91
250
<30





93
220
<30





95
180
10





96
310
<30





104
720
<30





110
170
<30





113
310
32





117
81
>1000





119
157
>1000





121
206
74





128
235
<30





136


233.2

23.5


142


250

<300


144
350
12





146
310
30





150

100





152


482.77

16


155


200

4


158


370.9




160


190

160


167


260

32


168


282.45

38.2


169


210

2.1


177


419.90

>100


185


453

45.4


187


180

>1000


188


257.3




190


269

51


193


317.57




198


477.39




199


627.48

>1000


200


364.3




201


250

<300


207


441.31




215


320

45


219


298.20




221


245.9

40


226


530

56


228


240

32


229


430

20


230


265.44

27


236


434.22

80


238


521.96




240


288.71

140


241


400

<10


242


308.45

14


243


165.81




244


238.89




245


628.25




246


301.36

61


247


422.93

81


248


275.96




249


271.29




250


331.21




251


336.34




252


248.51




263


399.85

77


267




130


269


172.35




270


250

297


272


285.35




273


197.06




274


224.99

>300


279




109


291


255.92




294




21


297


470.97

≦30


298


318059




304


194.54




316


452.88

45


317


311.08

24


318


439.94




320


215.3




322


440.86




323


217.91




325


317.57




328


531.7
423.1
96


331


537.3

10


334



345.13
100


337


299.50




340


216.53




348


343.24

200


365



521.8
200


366


427.95




369


583.16

8.3


370



226.54



379


370

43


380



250



381



441
4105


382

204.7

347
100


383



299
2


385




12.3


396



259.4666



397



251.7766



399


244.7508




400


230




402


345.045

12.1


404


433.3333




405


323.3333




406


235




407


310

48.94


408


430

21


409


420

149.8


410


233.3333

1.582


415


196.1812

28.4


416


288.6036

118.9


417


256.6667




418


196.6667

19.19


420


223.3333

0


421


193.3333

45.63


422


320




423


365

39.83


424



462.0976



429


180

83.75


431


280




440


696.6667

2.98


441


236.6667

205.8


445


406.6667




447


330




448


116.8948




456


261.1621




469


293.3333

108.2


470


210




471


296.6667




472


181.0865

34.24


473


243.3333




474


226.6667




480


548.575




484


380




487


340




493


271.4141

370.8


495



262.4635



517



309.141



522


666.6667

21.95


523



460.2177



525


477.2665

50.35


526


400

14.23


527


370.693




529


520

19.11


530


326.6667




535


335.0294




537



261.5724



541


320




546



282.0317



549


373.3333

242.7


551


239.0643




552


235.2857




555


296.6667

107


558


221.9818

4.74


559


231.6378




561


620




562


289.8854




569


1156.667




570



377.5594



575


246.6667




576



225.798



578


936.6667




583


613.3333

51.3


589


236.6667




590



220.4586



594



320



597


263.3333




599


116.6667




605


726.6667




608



442.1916



609



306.6667



611



176.7495



614



407.7118



621



256.6667



623



433.3333



624



310



625


403.3333




626



387.4854



627



446.6667



628



473.0586
88.4


629



153.3918
6.848


630


125.1944

47.07


631


156.9645




632



237.1158
29.28


633




204.5


634




137.5


638



341.3493
11.24


645



246.4648



646



276.7167
23.45


647



420.0246
150.7


648


366.0679




649



224.5026



654


293.3333




656



197.5908



657



357.6409



658



260.3278



659



251.6549





*Ieq refers to calculations based on the maximum current.


**AUC is the full area under the curve upon forskolin stimulation.






Information on protein binding of compounds can be retrieved from incubation of compounds in the presence of 40% human serum. For this purpose the differentiated cells are treated basolaterally with test compounds in medium containing 40% human serum (Sigma; H4522) for 24 hours. For electrophysiological recording, the human airway epithelia are mounted in the TECC heating plate and kept at 37° C. The epithelia are bathed in a NaCl-Ringer solution (120 mM NaCl, 25 mM NaHCO3, 1.2 mM CaCl2, 1.2 mM MgCl2, 0.8 mM KH2PO4, 0.8 mM K2HPO4, pH 7.4, 5 mM glucose) on both the basolateral and apical sides. Test compounds (corrector, co-corrector, 4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic acid, and potentiator, N-(3-carbamoyl-5,5,7,7-tetramethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl)-1H-pyrazole-5-carboxamide), are re-added to the recording solution prior to measurement. Apical amiloride is used to inhibit the endogenous ENaC currents while forskolin is applied on both apical and basolateral side to stimulate CFTR. Measurements are done during a 20 minute timeframe with recordings every 2 minutes. The increase in Ieq is used as a measure for the increased CFTR activity, EC50 values can be generated by measuring impact of different concentrations of compound on Ieq on primary cells, for this purpose each transwell is treated with a different compound concentration. Inh-172, an inhibitor specific for CFTR, is used to test the specificity of the tested compounds.
It is understood that the foregoing detailed description and accompanying examples are merely illustrative and are not to be taken as limitations upon the scope of the invention, which is defined solely by the appended claims and their equivalents. Various changes and modifications to the described embodiments will be apparent to those skilled in the art. Such changes and modifications, including without limitation those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, formulations, or methods, or any combination of such changes and modifications of use of the invention, may be made without departing from the spirit and scope thereof.








LENGTHY TABLES




The patent contains a lengthy table section. A copy of the table is available in electronic form from the USPTO web site (http://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US09890158B2). An electronic copy of the table will also be available from the USPTO upon request and payment of the fee set forth in 37 CFR 1.19(b)(3).

## Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof,




wherein
R1 is G1A, C1-C6 haloalkyl, or C1-C6 alkyl; wherein the C1-C6 haloalkyl and the C1-C6 alkyl are each optionally substituted with one G1A;
G1A, at each occurrence, is independently phenyl, 5-6 membered monocyclic heteroaryl, 4-7 membered monocyclic heterocycle, 5-11 membered fused bicyclic heterocycle, or C3-C6 monocyclic cycloalkyl; wherein each G1A is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of R1a and G1B;
G1B, at each occurrence, is independently 4-7 membered monocyclic heterocycle which is optionally substituted with 1, 2, 3, or 4 independently selected R1b groups;
R2 is hydrogen, C2-C4 alkenyl, C1-C6 alkyl, C1-C6 haloalkyl, —OR2xa, —N(R2xa)(R2xb), or G2A;
R2xa, at each occurrence, is independently C1-C6 alkyl, C1-C6 haloalkyl, or G2B;
R2xb is hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl;
G2A and G2B are each independently a 4-7 membered monocyclic heterocycle or a C3-C6 monocyclic cycloalkyl; wherein G2A and G2B are each optionally substituted with 1, 2, or 3 independently selected R2a groups;
R3 is G3A, -G3B-L1-G3C, -G3B-L3-G3C-G3E, —(C1-C6 alkylenyl)-G3D, —OR3a, or —N(R3a)(R3b);
R3a, at each occurrence, is independently G3D, C1-C6 haloalkyl, or C1-C6 alkyl; wherein the C1-C6 haloalkyl and the C1-C6 alkyl are each optionally substituted with one or two substituents independently selected from the group consisting of G3D, —OR3xa, and —N(R3xb)2;
R3xa and R3xb, at each occurrence, are each independently hydrogen, C1-C6 haloalkyl, C1-C6 alkyl, or G3D;
R3b is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl;
L1 is a bond, C1-C6 alkylenyl, (C1-C6 alkylenyl)r-L2-(C1-C6 alkylenyl)s, or O—(C1-C6 alkylenyl)-C(O), wherein the left end of the L1 moiety is attached to G3B;
L2 is O, N(Rx), C(O), N(Rx)C(O), or C(O)N(Rx); wherein each Rx is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl;
L3 is a bond or C1-C6 alkylenyl;
r is 0 or 1;
s is 0 or 1;
G3A, G3B, and G3C and each independently C3-C11 cycloalkyl, phenyl, 5-6 membered monocyclic heteroaryl, or 4-11 membered heterocycle; wherein G3A, G3B, and G3C are each optionally substituted with 1, 2, 3, or 4 independently selected Re groups;
G3D, at each occurrence, is independently C3-C8 monocyclic cycloalkyl, 4-7 membered monocyclic heterocycle, a 5-11 membered fused bicyclic heterocycle, or a 5-11 membered spiro heterocycle; wherein each G3D is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of Re and G3E;
G3E, at each occurrence, is independently C3-C8 monocyclic cycloalkyl or 4-7 membered monocyclic heterocycle; wherein each G3E is optionally substituted with 1, 2, 3, or 4 independently selected Re groups;
R4 is hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl;
R5 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, —N(R5ax)(R5bx), —OR5dx, or G5A; wherein the C1-C6 alkyl and the C1-C6 haloalkyl are each optionally substituted with one or two substituents independently selected from the group consisting of G5A, —CN, —N3, —OR5ax, —S(O)2R5ax, —S(O)2N(R5ax)(R5bx), —N(R5ax)(R5bx), —N(R5bx)S(O)2R5cx, —N(R5bx) C(O)R5cx, —N(R5bx)C(O)N(R5ax)(R5bx), —N(R5bx)C(O)OR5cx, —C(O)R5ax, —C(O)OR5ax, —C(O)N(R5bx)S(O)2R5cx, and —C(O)N(R5ax)(R5bx);
R5ax and R5bx, at each occurrence, are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, —OR5ex, —(C1-C6 alkylenyl)-OR5ex, G5A, or —(C1-C6 alkylenyl)-G5A;
R5cx, at each occurrence, is independently C1-C6 alkyl, C1-C6 haloalkyl, G5A, or —(C1-C6 alkylenyl)-G5A;
R5dx is C1-C6 alkyl, or C1-C6 haloalkyl;
R5ex is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl;
G5A, at each occurrence, is independently C3-C11 cycloalkyl, phenyl, 5-6 membered monocyclic heteroaryl, or 4-11 membered heterocycle; wherein each G5A is optionally substituted with 1, 2, 3, or 4 independently selected R5a groups;
R5a, at each occurrence, is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, oxo, G5B, —CN, NO2, —ORb, —OC(O)Rc, —OC(O)N(Rd)2, —SRb, —S(O)2Rb, —S(O)2N(Rd)2, —C(O)Rb, —C(O)ORb, —C(O)N(Rd)2, —C(O)N(Rd)S(O)2Rc, —N(Rd)2, —N(Rd)C(O)Rc, —N(Rd)S(O)2Rc, —N(Rd)C(O)O(Rb), —N(Rd)C(O)N(Rd)2, —N(Rd)S(O)2N(Rd)2, —(C1-C6 alkylenyl)-CN, —(C1-C6 alkylenyl)-G5B, —(C1-C6 alkylenyl)-ORb, —(C1-C6 alkylenyl)-OC(O)Rc, —(C1-C6 alkylenyl)-OC(O)N(Rd)2, —(C1-C6 alkylenyl)-SRb, —(C1-C6 alkylenyl)-S(O)2Rb, —(C1-C6 alkylenyl)-S(O)2N(Rd)2, —(C1-C6 alkylenyl)-C(O)Rb, —(C1-C6 alkylenyl)-C(O)ORb, —(C1-C6 alkylenyl)-C(O)N(Rd)2, —(C1-C6 alkylenyl)-C(O)N(Rd)S(O)2Rc, —(C1-C6 alkylenyl)-N(Rd)2, —(C1-C6 alkylenyl)-N(Rd)C(O)Rc, —(C1-C6 alkylenyl)-N(Rd)S(O)2Rc, —(C1-C6 alkylenyl)-N(Rd)C(O)O(Rc), —(C1-C6 alkylenyl)-N(Rd)C(O)N(Rd)2, or —(C1-C6 alkylenyl)-N(Rd)S(O)2N(Rd)2;
Rb and Rd, at each occurrence, are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, alkoxyalkyl, G5B, or —(C1-C6 alkylenyl)-G5B;
Rc, at each occurrence, is independently C1-C6 alkyl, C1-C6 haloalkyl, alkoxyalkyl, G5B, or —(C1-C6 alkylenyl)-G5B;
G5B, at each occurrence, is independently C3-C6 monocyclic cycloalkyl, phenyl, 5-6 membered monocyclic heteroaryl, or 4-7 membered monocyclic heterocycle; wherein each G5B is optionally substituted with 1, 2, 3, or 4 independently selected R5b groups;
Re, at each occurrence, is independently C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl, C1-C6 haloalkyl, halogen, oxo, —CN, —N3, —NO2, —ORf, —OC(O)Rg, —OC(O)NRfRh, —SRf, —S(O)2Rf, —S(O)2NRfRh, —C(O)Rf, —C(O)ORf, —C(O)NRfRh, —C(O)N(Rh)S(O)2Rf, —N(Rf)2, —N(Rh)C(O)Rh, —N(Rh)S(O)2Rg, —N(Rh)C(O)O(Rg), —N(Rh)C(O)NRfRh, or —N(Rh)S(O)2NRfRh; wherein the C1-C6 haloalkyl and the C1-C6 alkyl are each optionally substituted with 1 or 2 substituents independently selected from the group consisting of —CN, NO2, —ORf, —OC(O)Rg, —OC(O)NRfRh, —SRf, —S(O)2Rf, —S(O)2NRfRh, —C(O)Rf, —C(O)ORf, —C(O)NRfRh, —C(O)N(Rh)S(O)2Rf, —N(Rf)2, —N(Rh)C(O)Rg, —N(Rh)S(O)2Rg, —N(Rh)C(O)O(Rg), —N(Rh)C(O)NRfRh, and —N(Rh)S(O)2NRfRh;
Rf, at each occurrence, is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, —(C1-C6 alkylenyl)-CN, —(C1-C6 alkylenyl)-ORm, —(C1-C6 alkylenyl)-OC(O)Rn, —(C1-C6 alkylenyl)-OC(O)N(Rm)2, —(C1-C6 alkylenyl)-SRm, —(C1-C6 alkylenyl)-S(O)2Rm, —(C1-C6 alkylenyl)-S(O)2N(Rm)2, —(C1-C6 alkylenyl)-C(O)Rm, —(C1-C6 alkylenyl)-C(O)ORm, —(C1-C6 alkylenyl)-C(O)N(Rm)2, —(C1-C6 alkylenyl)-C(O)N(Rm)S(O)2Rn, —(C1-C6 alkylenyl)-N(Rm)2, —(C1-C6 alkylenyl)-N(Rm)C(O)Rn, —(C1-C6 alkylenyl)-N(Rm)S(O)2Rn, —(C1-C6 alkylenyl)-N(Rm)C(O)O(Rn), —(C1-C6 alkylenyl)-N(Rm)C(O)N(Rm)2, or —(C1-C6 alkylenyl)-N(Rm)S(O)2N(Rm)2 
Rg, at each occurrence, is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, —(C1-C6 alkylenyl)-CN, —(C1-C6 alkylenyl)-ORm, —(C1-C6 alkylenyl)-OC(O)Rn, —(C1-C6 alkylenyl)-OC(O)N(Rm)2, —(C1-C6 alkylenyl)-SRm, —(C1-C6 alkylenyl)-S(O)2Rm, —(C1-C6 alkylenyl)-S(O)2N(Rm)2, —(C1-C6 alkylenyl)-C(O)Rm, —(C1-C6 alkylenyl)-C(O)ORm, —(C1-C6 alkylenyl)-C(O)N(Rm)2, —(C1-C6 alkylenyl)-C(O)N(Rm)S(O)2Rn, —(C1-C6 alkylenyl)-N(Rm)2, —(C1-C6 alkylenyl)-N(Rm)C(O)Rn, —(C1-C6 alkylenyl)-N(Rm)S(O)2Rn, —(C1-C6 alkylenyl)-N(Rm)C(O)O(Rn), —(C1-C6 alkylenyl)-N(Rm)C(O)N(Rm)2, or —(C1-C6 alkylenyl)-N(Rm)S(O)2N(Rm)2;
Rh, at each occurrence, is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or —(C1-C6 alkylenyl)-ORm;
R1a, R1b, R2a, and R5b, at each occurrence, are each independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, oxo, —CN, NO2, —ORm, —OC(O)Rn, —OC(O)N(Rm)2, —SRm, —S(O)2Rm, —S(O)2N(Rm)2, —C(O)Rm, —C(O)ORm, —C(O)O(benzyl), —C(O)N(Rm)2, —C(O)N(Rm)S(O)2Rn, —N(Rm)2, —N(Rm)(alkoxyalkyl), —N(alkoxyalkyl)2, —N(Rm)C(O)Rn, —N(Rm)S(O)2Rn, —N(Rm)C(O)O(Rn), —N(Rm)C(O)N(Rm)2, —N(Rm)S(O)2N(Rm)2, —(C1-C6 alkylenyl)-CN, —(C1-C6 alkylenyl)-ORm, —(C1-C6 alkylenyl)-OC(O)Rn, —(C1-C6 alkylenyl)-OC(O)N(Rm)2, —(C1-C6 alkylenyl)-SRm, —(C1-C6 alkylenyl)-S(O)2Rm, —(C1-C6 alkylenyl)-S(O)2N(Rm)2, —(C1-C6 alkylenyl)-C(O)Rm, —(C1-C6 alkylenyl)-C(O)ORm, —(C1-C6 alkylenyl)-C(O)N(Rm)2, —(C1-C6 alkylenyl)-C(O)N(Rm)S(O)2Rn, —(C1-C6 alkylenyl)-N(Rm)2, —(C1-C6 alkylenyl)-N(Rm)C(O)Rn, —(C1-C6 alkylenyl)-N(Rm)S(O)2Rn, —(C1-C6 alkylenyl)-N(Rm)C(O)O(Rn), —(C1-C6 alkylenyl)-N(Rm)C(O)N(Rn)2, or —(C1-C6 alkylenyl)-N(Rm)S(O)2N(Rn)2;
Rm, at each occurrence, is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl;
Rn, at each occurrence, is independently C1-C6 alkyl or C1-C6 haloalkyl;
R6 is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; or
R5 and R6 together form a C1-C6 alkylenyl or —N(Rz)—(C1-C6 alkylenyl)- wherein the N(Rz) is attached to the S(O)2 moiety of formula (I); and
Rz is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R1 is G1A, C1-C6 haloalkyl, or C1-C6 alkyl.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R1 is G1A.

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R1 is G1A; wherein G1A is optionally substituted phenyl or optionally substituted 5-6 membered monocyclic heteroaryl.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R2 is C1-C6 alkyl, C1-C6 haloalkyl, —OR2xa, or G2A.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R2 is C1-C6 alkyl, C1-C6 haloalkyl, or G2A; and
G2A is an optionally substituted C3-C6 monocyclic cycloalkyl.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R2 is —OR2xa.

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R3 is G3A, -G3B-L1-G3C, or —OR3a.

9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R3 is G3A or -G3B-L1-G3C.

10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R3 is G3A; and
G3A is optionally substituted phenyl, optionally substituted 5-6 membered monocyclic heteroaryl, or optionally substituted 4-11 membered heterocycle.

11. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R3 is -G3B-L1-G3C;
G3B is phenyl, 5-6 membered monocyclic heteroaryl, or 4-7 membered monocyclic heterocycle; each of which is optionally substituted; and
G3C is C3-C6 monocyclic cycloalkyl, phenyl, 5-6 membered monocyclic heteroaryl, or 4-7 membered monocyclic heterocycle; each of which is optionally substituted.

12. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R3 is —OR3a; and
R3a is G3D, C1-C6 haloalkyl, or C1-C6 alkyl; wherein the C1-C6 haloalkyl and the C1-C6 alkyl are each substituted with one or two substituents independently selected from the group consisting of G3D, —OR3xa, and —N(R3xb)2.

13. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R5 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl; wherein the C1-C6 alkyl and the C1-C6 haloalkyl are each optionally substituted with one or two substituents independently selected from the group consisting of G5A, —CN, —N3, —OR5ax, —S(O)2R5ax, —S(O)2N(R5ax)(R5bx), —N(R5ax)(R5bx), —N(R5bx)S(O)2R5cx, —N(R5bx)C(O)R5cx, —N(R5bx)C(O)N(R5ax)(R5bx), —N(R5bx)C(O)OR5cx, —C(O)R5ax, —C(O)OR5ax, —C(O)N(R5bx)S(O)2R5cx, and —C(O)N(R5ax)(R5bx).

14. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R5 is —N(R5ax)(R5bx).

15. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R5 is G5A.

16. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R1 is G1A, C1-C6 haloalkyl, or C1-C6 alkyl; and
R2 is C1-C6 alkyl, C1-C6 haloalkyl, or G2A.

17. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R1 is G1A;
R2 is C1-C6 alkyl or G2A; and
R3 is G3A, -G3B-L1-G3C, or —OR3a.

18. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R1 is G1A;
R2 is C1-C6 alkyl or G2A; and
R5 is C1-C6 alkyl or C1-C6 haloalkyl.

19. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R1 is G1A;
R2 is C1-C6 alkyl or G2A; and
R5 is C1-C6 alkyl which is substituted with one substituent selected from the group consisting of G5A, —CN, —N3, —OR5ax, —N(R5ax)(R5bx), —N(R5bx)C(O)R5cx, —N(R5bx)C(O)OR5cx, —C(O)OR5ax, and —C(O)N(R5ax)(R5bx).

20. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R1 is G1A;
R2 is C1-C6 alkyl or G2A; and
R5 is —N(R5ax)(R5bx).

21. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R1 is G1A;
R2 is C1-C6 alkyl or G2A; and
R5 is G5A.

22. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R1 is G1A; wherein G1A is optionally substituted phenyl, or optionally substituted 5-6 membered monocyclic heteroaryl;
R2 is C1-C6 alkyl or G2A; wherein G2A is an optionally substituted C3-C6 monocyclic cycloalkyl;
R3 is G3A, -G3B-L1-G3C, or —OR3a; and
R5 is C1-C6 alkyl which is substituted with one substituent selected from the group consisting of G5A, —CN, —N3, —OR5ax, —N(R5ax)(R5bx), —N(R5bx)C(O)R5cx, —N(R5bx)C(O)OR5cx, —C(O)OR5ax, and —C(O)N(R5ax)(R5bx).

23. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R1 is G1A; wherein G1A is optionally substituted phenyl or optionally substituted 5-6 membered monocyclic heteroaryl;
R2 is C1-C6 alkyl or G2A; wherein G2A is an optionally substituted C3-C6 monocyclic cycloalkyl;
R3 is G3A, -G3B-L1-G3C, or —OR3a; and
R5 is C1-C6 alkyl or C1-C6 haloalkyl.

24. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R1 is G1A; wherein G1A is optionally substituted phenyl or optionally substituted 5-6 membered monocyclic heteroaryl;
R2 is C1-C6 alkyl, or G2A; wherein G2A is an optionally substituted C3-C6 monocyclic cycloalkyl;
R3 is G3A, -G3B-L1-G3C, or —OR3a; and
R5 is —N(R5ax)(R5bx) or —OR5dx.

25. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R1 is G1A; wherein G1A is optionally substituted phenyl or optionally substituted 5-6 membered monocyclic heteroaryl;
R2 is C1-C6 alkyl, or G2A; wherein G2A is an optionally substituted C3-C6 monocyclic cycloalkyl;
R3 is G3A, -G3B-L1-G3C, or —OR3a; and
R5 is G5A.

26. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R3 is -G3B-L3-G3C-G3E;
G3B is phenyl, 5-6 membered heteroaryl, or 4-11 membered heterocycle; each of which is optionally substituted;
G3C is optionally substituted 4-11 membered heterocycle; and
G3E is optionally substituted C3-C8 monocyclic cycloalkyl.

27. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R1 is G1A; wherein G1A is phenyl, 5-6 membered monocyclic heteroaryl, or C3-C6 monocyclic cycloalkyl; each of which is optionally substituted;
R2 is C1-C6 alkyl, —OR2xa, or G2A; wherein G2A is an optionally substituted C3-C6 monocyclic cycloalkyl; and
R3 is G3A, -G3B-L1-G3C, -G3B-L3-G3C-G3E, —(C1-C6 alkylenyl)-G3D, or —OR3a.

28. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R1 is G1A; wherein G1A is phenyl, 5-6 membered monocyclic heteroaryl, or C3-C6 monocyclic cycloalkyl; each of which is optionally substituted;
R2 is C1-C6 alkyl, —OR2xa, or G2A; wherein G2A is an optionally substituted C3-C6 monocyclic cycloalkyl;
R3 is G3A, -G3B-L1-G3C, -G3B-L3-G3C-G3E, —(C1-C6 alkylenyl)-G3D, or —OR3a; and
R5 is C1-C6 alkyl or C1-C6 haloalkyl.

29. The compound claim 1 or a pharmaceutically acceptable salt thereof, wherein
R6 is hydrogen.

30. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R6 is C1-C6 alkyl or C1-C6 haloalkyl.

31. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R5 and R6 together form a C1-C6 alkylenyl a —N(Rz)—(C1-C6 alkylenyl)- wherein the N(Rz) is attached to the S(O)2 moiety of formula (I).

32. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
N-(methanesulfonyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(benzenesulfonyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-methyl-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-N-(trifluoromethanesulfonyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(cyclopropanesulfonyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(ethanesulfonyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(methanesulfonyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1-[3-(trifluoromethoxy)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[4-(dimethylamino)phenyl]-N-(methanesulfonyl)-1-phenyl-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(methanesulfonyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-cyclohexyl-4-[2-(dimethylamino)pyrimidin-5-yl]-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-[3-(azetidin-1-yl)phenyl]-N-(methanesulfonyl)-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-cyclohexyl-N-(methanesulfonyl)-4-[2-(morpholin-4-yl)pyrimidin-5-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-tert-butyl-1-cyclopentyl-N-(methanesulfonyl)-4-[6-(morpholin-4-yl)pyridin-3-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(methanesulfonyl)-3-methyl-1-phenyl-4-(piperidin-1-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(methanesulfonyl)-4-(4-methoxyphenyl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(ethanesulfonyl)-4-(4-methoxyphenyl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(methanesulfonyl)-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1-[3-(pyrrolidin-1-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[4-(dimethylamino)phenyl]-N-(methanesulfonyl)-1-(6-methoxypyridin-3-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-(3-chloro-4-methylphenyl)-N-(methanesulfonyl)-4-(4-methoxyphenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(ethanesulfonyl)-3-methyl-1-phenyl-4-(piperidin-1-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(methanesulfonyl)-4-[2-(morpholin-4-yl)pyrimidin-5-yl]-1-phenyl-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-(2,4-difluorophenyl)-N-(methanesulfonyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-cyclohexyl-4-[6-(dimethylamino)pyridin-3-yl]-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-(3,5-difluorophenyl)-N-(methanesulfonyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-(3,5-dimethylphenyl)-N-(methanesulfonyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-(3,4-difluorophenyl)-N-(methanesulfonyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[4-(dimethylamino)phenyl]-N-(methanesulfonyl)-3-methyl-1-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(methanesulfonyl)-4-(4-methoxyphenyl)-3-methyl-1-(3-methylphenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(ethanesulfonyl)-4-(4-methoxyphenyl)-3-methyl-1-(3-methylphenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[2-(dimethylamino)pyrimidin-5-yl]-N-(methanesulfonyl)-1-[3-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[2-(dimethylamino)pyrimidin-5-yl]-N-(ethanesulfonyl)-1-[3-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[6-(dimethylamino)pyridin-3-yl]-N-(methanesulfonyl)-1-[3-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[6-(dimethylamino)pyridin-3-yl]-N-(ethanesulfonyl)-1-[3-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[4-(dimethylamino)phenyl]-N-(methanesulfonyl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(methanesulfonyl)-4-[6-(morpholin-4-yl)pyridin-3-yl]-1-phenyl-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(ethanesulfonyl)-4-[6-(morpholin-4-yl)pyridin-3-yl]-1-phenyl-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(methanesulfonyl)-1-[3-(3-methoxyazetidin-1-yl)phenyl]-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(methanesulfonyl)-3-methyl-4-[6-(morpholin-4-yl)pyridin-3-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-(4,4-difluorocyclohexyl)-N-(methanesulfonyl)-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(methanesulfonyl)-4-[4-(morpholin-4-yl)phenyl]-1-(oxan-3-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(ethanesulfonyl)-4-[4-(morpholin-4-yl)phenyl]-1-(oxan-3-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-h]pyridine-6-carboxamide;
4-{4-[3-(dimethylamino)azetidin-1-yl]phenyl}-N-(methanesulfonyl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-{4-[3-(dimethylamino)azetidin-1-yl]phenyl}-N-(ethanesulfonyl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-[3-(3,3-dimethylazetidin-1-yl)phenyl]-N-(methanesulfonyl)-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-cyclohexyl-N-(methanesulfonyl)-4-[6-(morpholin-4-yl)pyridin-3-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-cyclohexyl-N-(ethanesulfonyl)-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-[3-(3-fluoropyrrolidin-1-yl)phenyl]-N-(methanesulfonyl)-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-cyclohexyl-N-(methanesulfonyl)-3-methyl-4-[6-(morpholin-4-yl)pyridin-3-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-cyclohexyl-N-(ethanesulfonyl)-3-methyl-4-[6-(morpholin-4-yl)pyridin-3-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-cyclohexyl-4-[2-(dimethylamino)pyrimidin-5-yl]-N-(methanesulfonyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-cyclohexyl-4-[2-(dimethylamino)pyrimidin-5-yl]-N-(ethanesulfonyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-cyclohexyl-N-(methanesulfonyl)-4-{6-[methyl(oxan-4-yl)amino]pyridin-3-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
methyl 3-{1-cyclohexyl-4-[2-(dimethylamino)pyrimidin-5-yl]-6-[(ethanesulfonyl)carbamoyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}azetidine-1-carboxylate;
1-[3-(dimethylamino)phenyl]-N-(methanesulfonyl)-4-[6-(morpholin-4-yl)pyridin-3-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-[3-(dimethylamino)phenyl]-N-(ethanesulfonyl)-4-[6-(morpholin-4-yl)pyridin-3-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-cyclopentyl-4-[6-(dimethylamino)pyridin-3-yl]-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-cyclopentyl-4-[6-(dimethylamino)pyridin-3-yl]-N-(ethanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(methanesulfonyl)-3-methyl-4-[6-(morpholin-4-yl)pyridin-3-yl]-1-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(ethanesulfonyl)-3-methyl-4-[6-(morpholin-4-yl)pyridin-3-yl]-1-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-[3-(dimethylamino)phenyl]-N-(methanesulfonyl)-4-[2-(morpholin-4-yl)pyrimidin-5-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-(2,4-difluorophenyl)-N-(methanesulfonyl)-3-methyl-4-[6-(morpholin-4-yl)pyridin-3-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-(2,4-difluorophenyl)-N-(ethanesulfonyl)-3-methyl-4-[6-(morpholin-4-yl)pyridin-3-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-[3-(dimethylamino)phenyl]-N-(ethanesulfonyl)-4-[2-(morpholin-4-yl)pyrimidin-5-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(methanesulfonyl)-4-{6-[(2-methoxyethyl)(methyl)amino]pyridin-3-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-cyclohexyl-4-[6-(3,3-difluoropyrrolidin-1-yl)pyridin-3-yl]-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-(3-chlorophenyl)-N-(methanesulfonyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-(3-chlorophenyl)-N-(ethanesulfonyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-(3-fluorophenyl)-N-(methanesulfonyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(ethanesulfonyl)-1-(3-fluorophenyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(methanesulfonyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1-[4-(trifluoromethoxy)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(ethanesulfonyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1-[4-(trifluoromethoxy)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-3-cyclobutyl-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(methanesulfonyl)-1-(3-methoxyphenyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(ethanesulfonyl)-1-(3-methoxyphenyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(methanesulfonyl)-4-{6-[methyl(oxan-4-yl)amino]pyridin-3-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(methanesulfonyl)-4-{4-[(2-methoxyethyl)(methyl)amino]phenyl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(methanesulfonyl)-1-{3-[(2-methoxyethyl)(methyl)amino]phenyl}-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-[3-(dimethylamino)phenyl]-4-[2-(dimethylamino)pyrimidin-5-yl]-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-[3-(dimethylamino)phenyl]-4-[2-(dimethylamino)pyrimidin-5-yl]-N-(ethanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-(4-acetamidophenyl)-1-cyclohexyl-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[4-(4-cyanopiperidin-1-yl)phenyl]-1-cyclohexyl-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[4-(4-cyanopiperidin-1-yl)phenyl]-1-[3-(dimethylamino)phenyl]-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-[3-(dimethylamino)phenyl]-N-(methanesulfonyl)-4-{4-[(2-methoxyethyl)(methyl)amino]phenyl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-1-[3-(dimethylamino)phenyl]-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-[3-(dimethylamino)phenyl]-N-(methanesulfonyl)-4-{6-[(2-methoxyethyl)(methyl)amino]pyridin-3-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-N-(methanesulfonyl)-1-[3-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(methanesulfonyl)-4-{6-[(2-methoxyethyl)(methyl)amino]pyridin-3-yl}-1-[3-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(methanesulfonyl)-4-{6-[methyl(oxan-4-yl)amino]pyridin-3-yl}-1-[3-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(methanesulfonyl)-4-{4-[(2-methoxyethyl)(methyl)amino]phenyl}-1-[3-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-[3-(dimethylamino)phenyl]-N-(methanesulfonyl)-4-{6-[methyl(oxan-4-yl)amino]pyridin-3-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-cyclohexyl-N-(ethanesulfonyl)-4-{6-[methyl(oxan-4-yl)amino]pyridin-3-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-[3-(dimethylamino)phenyl]-N-(methanesulfonyl)-4-{2-[methyl(oxan-4-yl)amino]pyrimidin-5-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-cyclohexyl-3-cyclopropyl-4-[6-(dimethylamino)pyridin-3-yl]-N-(ethanesulfonyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-cyclohexyl-4-[6-(2,6-dimethylmorpholin-4-yl)pyridin-3-yl]-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-cyclohexyl-4-[6-(2,2-dimethylmorpholin-4-yl)pyridin-3-yl]-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[2-(4-cyanopiperidin-1-yl)pyrimidin-5-yl]-1-[3-(dimethylamino)phenyl]-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-[3-(dimethylamino)phenyl]-N-(methanesulfonyl)-4-{4-[methyl(oxan-4-yl)amino]phenyl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(methanesulfonyl)-4-{4-[methyl(oxan-4-yl)amino]phenyl}-1-[3-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[6-(4-cyano-4-methylpiperidin-1-yl)pyridin-3-yl]-1-cyclohexyl-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[2-(4-cyanopiperidin-1-yl)pyrimidin-5-yl]-N-(methanesulfonyl)-1-[3-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-{4-[3-(dimethylamino)pyrrolidin-1-yl]phenyl}-N-(methanesulfonyl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(methanesulfonyl)-1-(3-methylphenyl)-4-(piperidin-1-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(ethanesulfonyl)-1-(3-methylphenyl)-4-(piperidin-1-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[4-(4-cyanopiperidin-1-yl)phenyl]-3-cyclobutyl-1-cyclohexyl-N-(methanesulfonyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-3-cyclobutyl-1-cyclohexyl-N-(methanesulfonyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-[3-(3-hydroxyazetidine-1-yl)phenyl]-N-(methanesulfonyl)-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-cyclohexyl-N-(methanesulfonyl)-4-[6-(3-methoxypyrrolidin-1-yl)pyridin-3-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
methyl 3-{4-(4-acetamidophenyl)-1-(3,5-difluorophenyl)-6-[(methanesulfonyl)carbamoyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}azetidine-1-carboxylate;
1-cyclohexyl-4-[6-(3-fluoropiperidin-1-yl)pyridin-3-yl]-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(methanesulfonyl)-4-{4-[(2-methoxyethyl)(methyl)amino]phenyl}-3-(propan-2-yl)-1-[3-(pyrrolidin-1-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(methanesulfonyl)-4-{4-[methyl(oxan-4-yl)amino]phenyl}-3-(propan-2-yl)-1-[3-(pyrrolidin-1-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(methanesulfonyl)-4-{4-[methyl(oxan-4-yl)amino]phenyl}-1-[3-(pyrrolidin-1-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(ethanesulfonyl)-4-[2-(morpholin-4-yl)pyrimidin-5-yl]-1-phenyl-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-(2,4-difluorophenyl)-N-(ethanesulfonyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-(3-chloro-4-methylphenyl)-N-(ethanesulfonyl)-4-(4-methoxyphenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-(3,5-dimethylphenyl)-N-(ethanesulfonyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-(3,4-difluorophenyl)-N-(ethanesulfonyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(methanesulfonyl)-4-(4-methoxypiperidin-1-yl)-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(ethanesulfonyl)-4-(4-methoxypiperidin-1-yl)-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[2-(4-cyanopiperidin-1-yl)pyrimidin-5-yl]-1-cyclohexyl-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-cyclohexyl-N-(methanesulfonyl)-4-{2-[(2-methoxyethyl)(methyl)amino]pyrimidin-5-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-{6-[bis(2-methoxyethyl)amino]pyridin-3-yl}-1-cyclohexyl-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-cyclohexyl-N-(methanesulfonyl)-4-{6-[methyl(oxolan-3-yl)amino]pyridin-3-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-cyclohexyl-N-(methanesulfonyl)-4-{2-[methyl(oxan-4-yl)amino]pyrimidin-5-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-N-(methanesulfonyl)-3-(propan-2-yl)-1-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-[6-(dimethylamino)pyridin-2-yl]-N-(methanesulfonyl)-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(methanesulfonyl)-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1-[3-(trifluoromethoxy)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-(3,4-difluorophenyl)-N-(methanesulfonyl)-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(methanesulfonyl)-4-[4-(morpholin-4-yl)phenyl]-1-[6-(morpholin-4-yl)pyridin-2-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-(2,6-difluoro-4-methoxyphenyl)-1-(3-fluoro-5-methoxyphenyl)-N-(methanesulfonyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[4-(4-cyanopiperidin-1-yl)phenyl]-1-(3,5-difluorophenyl)-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[4-(4-cyanopiperidin-1-yl)phenyl]-1-(3-fluorophenyl)-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(methanesulfonyl)-4-{4-[(2-methoxyethyl)(methyl)amino]phenyl}-3-(propan-2-yl)-1-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(methanesulfonyl)-4-{6-[methyl(oxan-4-yl)amino]pyridin-3-yl}-3-(propan-2-yl)-1-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-(4-fluorophenyl)-N-(methanesulfonyl)-4-{2-[methyl(oxan-4-yl)amino]pyrimidin-5-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[4-(4-cyanopiperidin-1-yl)phenyl]-N-(methanesulfonyl)-3-(propan-2-yl)-1-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(methanesulfonyl)-4-[4-(morpholin-4-yl)phenyl]-1-[2-(morpholin-4-yl)pyridin-4-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(methanesulfonyl)-3-(1-methylcyclobutyl)-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(ethanesulfonyl)-3-(1-methylcyclobutyl)-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[2-(4-cyanopiperidin-1-yl)pyrimidin-5-yl]-1-(2,4-difluorophenyl)-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-1-(2,4-difluorophenyl)-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[4-(4-cyanopiperidin-1-yl)phenyl]-1-(2,4-difluorophenyl)-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(methanesulfonyl)-4-(4-methoxypiperidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(1,1-dioxo-1λ6-thiolane-3-sulfonyl)-4-(4-methoxypiperidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-[3-(dimethylamino)phenyl]-N-(methanesulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-N-(methanesulfonyl)-1-(oxan-3-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(2-methoxyethanesulfonyl)-4-(4-methoxypiperidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-(4-methoxypiperidin-1-yl)-1-phenyl-N-(3,3,3-trifluoropropane-1-sulfonyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(methanesulfonyl)-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-(1,1-difluoro-5-azaspiro[2.4]heptan-5-yl)-N-(methanesulfonyl)-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-cyclohexyl-N-(methanesulfonyl)-4-(4-methoxypiperidin-1-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(methanesulfonyl)-1-phenyl-4-{4-[(propan-2-yl)oxy]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(methanesulfonyl)-1-phenyl-4-(4-propoxypiperidin-1-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(methanesulfonyl)-4-[3-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(methanesulfonyl)-4-{4-[2-oxo-2-(pyrrolidin-1-yl)ethoxy]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-[3-(dimethylamino)phenyl]-N-(methanesulfonyl)-4-(4-methoxypiperidin-1-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(methanesulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-[3-(dimethylamino)phenyl]-N-(methanesulfonyl)-4-(piperidin-1-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-N-(methanesulfonyl)-3-(propan-2-yl)-1-[2-(pyrrolidin-1-yl)pyridin-4-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(methanesulfonyl)-4-(1-oxa-7-azaspiro[3.5]nonan-7-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-(4-cyanopiperidin-1-yl)-1-[3-(dimethylamino)phenyl]-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(methanesulfonyl)-4-[4-(2-methoxyethyl)piperidin-1-yl]-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(methanesulfonyl)-4-(3-methoxypiperidin-1-yl)-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(ethanesulfonyl)-4-(3-methoxypiperidin-1-yl)-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[4-(fluoromethyl)piperidin-1-yl]-N-(methanesulfonyl)-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(methanesulfonyl)-4-[4-(methanesulfonyl)piperidin-1-yl]-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(methanesulfonyl)-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-(4-fluorophenyl)-N-(methanesulfonyl)-4-(4-methoxypiperidin-1-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-(4-fluorophenyl)-N-(methanesulfonyl)-4-[4-methoxymethyl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[4-(4-cyanopiperidin-1-yl)phenyl]-N-(methanesulfonyl)-3-(propan-2-yl)-1-[2-(pyrrolidin-1-yl)pyridin-4-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(methanesulfonyl)-4-[(2-methoxyethyl)(methyl)amino]-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(methanesulfonyl)-1-(3-methylphenyl)-4-(8-oxa-2-azaspiro[4.5]decan-2-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-(4-butoxypiperidin-1-yl)-1-(4-fluorophenyl)-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-(4-fluorophenyl)-N-(methanesulfonyl)-4-(4-methoxy-4-methylpiperidin-1-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
2-[(2-{[3-cyclobutyl-4-(4-methoxypiperidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carbonyl]sulfamoyl}ethyl)carbamoyl]benzoic acid;
1-(4-fluorophenyl)-N-(methanesulfonyl)-4-[4-(2-methylpropoxy)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-(4-methoxypiperidin-1-yl)-1-phenyl-N-(2,2,2-trifluoroethanesulfonyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-(4-fluorophenyl)-N-(methanesulfonyl)-4-(1-oxa-7-azaspiro[3.5]nonan-7-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[3-(difluoromethyl)piperidin-1-yl]-1-(4-fluorophenyl)-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-(4-fluorophenyl)-N-(methanesulfonyl)-4-(6-oxa-2-azaspiro[3.5]nonan-2-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-(4-fluorophenyl)-N-(methanesulfonyl)-4-(1-oxa-8-azaspiro[4.5]decan-8-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-(cyclohexylmethoxy)-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(methanesulfonyl)-1-phenyl-4-(piperidin-1-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(methanesulfonyl)-4-[4-(2-methoxyethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-(2-azaspiro[3.4]octan-2-yl)-3-cyclobutyl-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(methanesulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-(3-azabicyclo[3.1.0]hexan-3-yl)-3-cyclobutyl-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(methanesulfonyl)-4-(4-methoxypiperidin-1-yl)-1-[2-(morpholin-4-yl)pyridin-4-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(methanesulfonyl)-4-(4-methoxypiperidin-1-yl)-3-(propan-2-yl)-1-[2-(pyrrolidin-1-yl)pyridin-4-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-3-cyclobutyl-N-(methanesulfonyl)-1-[2-(pyrrolidin-1-yl)pyridin-4-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(methanesulfonyl)-4-[4-(methanesulfonyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-(4-cyanopiperidin-1-yl)-3-cyclobutyl-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-(2-azaspiro[3.5]nonan-2-yl)-3-cyclobutyl-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(methanesulfonyl)-4-[3-(methoxymethyl)azetidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-N-(methanesulfonyl)-3-(cis-3-methoxycyclobutyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-3-(3,3-difluorocyclobutyl)-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-3-(3,3-dimethylcyclobutyl)-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-3-(3-fluorocyclobutyl)-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(methanesulfonyl)-4-[2-(oxan-4-yl)ethoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-[(2S)-2-fluoro-2-(oxan-4-yl)ethoxy]-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(methanesulfonyl)-4-[(oxan-4-yl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-3-cyclobutyl-N-(methanesulfonyl)-1-[2-(morpholin-4-yl)pyridin-4-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-(1,1-difluoro-5-azaspiro[2.4]heptan-5-yl)-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(methanesulfonyl)-4-(5-oxa-2-azaspiro[3.5]nonan-2-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(methanesulfonyl)-4-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-(5-azaspiro[2.5]octan-5-yl)-3-cyclobutyl-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(methanesulfonyl)-4-[(2-methoxyethyl)(methyl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-(4-methoxypiperidin-1-yl)-N-(oxane-4-sulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
benzyl 4-{[3-cyclobutyl-4-(4-methoxypiperidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carbonyl]sulfamoyl}piperidine-1-carboxylate;
4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-3-(cis-3-fluorocyclobutyl)-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-3-(trans-3-fluorocyclobutyl)-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(methanesulfonyl)-4-[(cis-4-methoxycyclohexyl)oxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(methanesulfonyl)-4-[(trans-4-methoxycyclohexyl)oxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-{4-[(benzyloxy)methyl]piperidin-1-yl}-3-cyclobutyl-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-(2-azaspiro[3.3]heptan-2-yl)-3-cyclobutyl-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
methyl 5-{3-cyclobutyl-6-[(methanesulfonyl)carbamoyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl}octahydro-1H-pyrrolo[3, 2-c]pyridine-1-carboxylate;
4-(1-acetyloctahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)-3-cyclobutyl-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(methanesulfonyl)-4-(4-methoxypiperidin-1-yl)-1-[6-(morpholin-4-yl)pyridin-2-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-cyclohexyl-N-(methanesulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-{4-[(1S)-2-(dimethylamino)-1-fluoroethyl]piperidin-1-yl}-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-[4-(fluoromethyl)piperidin-1-yl]-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-(4-fluorophenyl)-N-(methanesulfonyl)-4-[4-(2-methoxypropan-2-yl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-(3-azaspiro[5.5]undecan-3-yl)-3-cyclobutyl-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-(3,4-difluorophenyl)-N-(ethanesulfonyl)-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(ethanesulfonyl)-1-(3-fluorophenyl)-4-{6-[methyl(oxan-4-yl)amino]pyridin-3-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(cyclopropanesulfonyl)-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(2-methoxyethanesulfonyl)-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-N-(methanesulfonyl)-1-[2-(morpholin-4-yl)pyridin-4-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-[4-(cyclopentyloxy)piperidin-1-yl]-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-[4-(cyclohexyloxy)piperidin-1-yl]-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-[4-(cyclopropylmethoxy)piperidin-1-yl]-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(2-methoxyethanesulfonyl)-4-(4-methoxyphenyl)-3-methyl-1-(2-methylpropyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(2-methoxyethanesulfonyl)-4-[4-(morpholin-4-yl)phenyl]-1-(oxolan-3-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(2-methoxyethanesulfonyl)-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(2-methoxyethanesulfonyl)-4-(4-methoxyphenyl)-3-methyl-1-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-cyclopropyl-N-(2-methoxyethanesulfonyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-(4-fluorophenyl)-N-(2-methoxyethanesulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-[(2R)-2-fluoro-2-(oxan-4-yl)ethoxy]-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-[(3,3-difluorocyclopentyl)methoxy]-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-cyclohexyl-N-(cyclopropanesulfonyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-(4-cyanopiperidin-1-yl)-1-(4-fluorophenyl)-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(methanesulfonyl)-4-[4-(1-methoxyethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(methanesulfonyl)-1-phenyl-4-[4-(1,1,1-trifluoro-2-methoxypropan-2-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-[2-(1,1-dioxo-1λ6,4-thiazinan-4-yl)ethoxy]-N-(methanesufonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-[4-(hydroxymethyl)piperidin-1-yl]-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-N-(1-methyl-1H-pyrazole-4-sulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-{6-[bis(2-methoxyethyl)amino]pyridin-3-yl}-3-cyclobutyl-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(methanesulfonyl)-4-[4-methoxy-4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(methanesulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1-[2-(morpholin-4-yl)pyridin-4-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(2-methoxyethanesulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1-[2-(morpholin-4-yl)pyridin-4-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(1,2-dimethyl-1H-imidazole-4-sulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-cyclohexyl-N-(2-methoxyethanesulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-{6-[bis(2-methoxyethyl)amino]pyridin-3-yl}-N-(methanesulfonyl)-1-[2-(morpholin-4-yl)pyridin-4-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-N-(1H-pyrazole-4-sulfonyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(methanesulfonyl)-4-[(3-methyloxetan-3-yl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-{4-[(1,1-dioxo-1λ6,4-thiazinan-4-yl)methyl]-4-methoxypiperidin-1-yl}-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(2-methoxyethanesulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-N-(methanesulfonyl)-3-(trans-3-methylcyclobutyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-N-(methanesulfonyl)-1-phenyl-3-[(piperidin-4-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
tert-butyl 4-({4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-6-[(methanesulfonyl)carbamoyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridin-3-yl}oxy)piperidine-1-carboxylate;
3-cyclobutyl-N-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethanesulfonyl]-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(2-aminoethanesulfonyl)-3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-(cyclobutylmethyl)-N-(methanesulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-(cyclobutylmethyl)-N-(2-methoxyethanesulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(methanesulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1-(2-methylpropyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(2-methoxyethanesulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1-(2-methylpropyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-(4-fluorophenyl)-N-(methanesulfonyl)-3-(propan-2-yl)-4-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-N-[2-(morpholin-4-yl)ethanesulfonyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(methanesulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(2-methoxyethanesulfonyl)-4-[(3-methyloxetan-3-yl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(methanesulfonyl)-1-phenyl-4-[4-(propan-2-yl)piperazin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(2-methoxyethanesulfonyl)-1-phenyl-4-[4-(propan-2-yl)piperazin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-(4-fluorophenyl)-4-[4-(methoxymethyl)piperidin-1-yl]-N-[3-(morpholin-4-yl)propane-1-sulfonyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-[2-(dimethylamino)ethanesulfonyl]-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[(1-acetyl-4-fluoropiperidin-4-yl)methoxy]-3-cyclobutyl-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-N-(2-methoxyethanesulfonyl)-3-[(oxolan-3-yl)oxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-N-(2-methoxyethanesulfonyl)-3-(trans-3-methylcyclobutyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-N-(methanesulfonyl)-3-[(oxolan-3-yl)oxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-[3-(dimethylamino)phenyl]-N-(methanesulfonyl)-4-[(oxan-4-yl)methoxy]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(methanesulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1-[2-(morpholin-4-yl)pyrimidin-4-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-(4-cyclobutylpiperazin-1-yl)-1-(4-fluorophenyl)-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(methanesulfonyl)-4-[3-(morpholin-4-yl)propoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-[(3,3-difluoro-1-methylcyclobutyl)methoxy]-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(methanesulfonyl)-4-[(oxolan-2-yl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-(4-fluorophenyl)-N-(methanesulfonyl)-4-[(oxan-4-yl)methoxy]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-(4-fluorophenyl)-N-(methanesulfonyl)-4-[2-(oxan-4-yl)ethoxy]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-N-(1-methyl-1H-imidazole-4-sulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(3,5-dimethyl-1,2-oxazole-4-sulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
methyl 3-({3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carbonyl}sulfamoyl)propanoate;
3-({3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carbonyl}sulfamoyl)propanoic acid;
N-[3-(dimethylamino)propane-1-sulfonyl]-1-(4-fluorophenyl)-4-[4-(methoxymethyl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-(4-fluorophenyl)-4-[4-(methoxymethyl)piperidin-1-yl]-3-(propan-2-yl)-N-[3-(pyrrolidin-1-yl)propane-1-sulfonyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-(4-fluorophenyl)-N-(methanesulfonyl)-4-[3-(morpholin-4-yl)propoxy]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-(4-fluorophenyl)-N-(methanesulfonyl)-4-[(3-methyloxetan-3-yl)methoxy]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(methanesulfonyl)-4-[4-(2-methoxypropan-2-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-(4-fluorophenyl)-N-(methanesulfonyl)-4-[(oxolan-2-yl)methoxy]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[(1-acetylpiperidin-4-yl)methoxy]-3-cyclobutyl-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
methyl 4-[({3-cyclobutyl-6-[(methanesulfonyl)carbamoyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl}oxy)methyl]piperidine-1-carboxylate;
3-cyclobutyl-N-[3-(dimethylamino)-3-oxopropane-1-sulfonyl]-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[3-(dimethylamino)propoxy]-1-(4-fluorophenyl)-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-N-(methanesulfonyl)-3-[(oxetan-3-yl)oxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-(4-fluorophenyl)-N-(methanesulfonyl)-4-[(2-methoxyethyl)(methyl)amino]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-[3-(azetidin-1-yl)propane-1-sulfonyl]-1-(4-fluorophenyl)-4-[4-(methoxymethyl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-[3-(dimethylamino)propoxy]-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-(4-fluorophenyl)-4-[4-(2-hydroxypropan-2-yl)piperidin-1-yl]-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-(4-fluorophenyl)-N-(methanesulfonyl)-4-[2-(1-methylpiperidin-2-yl)ethoxy]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[(3,3-difluoro-1-methylcyclobutyl)methoxy]-1-(4-fluorophenyl)-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-(4-fluorophenyl)-N-(methanesulfonyl)-4-[3-(piperidin-1-yl)propoxy]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[(1-acetyl-4-fluoropiperidin-4-yl)methoxy]-1-(4-fluorophenyl)-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-(4-fluorophenyl)-N-(methanesulfonyl)-4-{2-[(oxetan-3-yl)(propan-2-yl)amino]ethoxy}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-(4-fluorophenyl)-N-(methanesulfonyl)-3-(propan-2-yl)-4-{[4-(propan-2-yl)morpholin-3-yl]methoxy}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[(1,3-dimethoxypropan-2-yl)oxy]-1-(4-fluorophenyl)-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[(1,4-dioxan-2-yl)methoxy]-1-(4-fluorophenyl)-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-(4-fluorophenyl)-N-(methanesulfonyl)-4-{2-[(oxetan-3-yl)oxy]ethoxy}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(methanesulfonyl)-1-phenyl-4-[3-(piperidin-1-yl)propoxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(2-methoxyethanesulfonyl)-4-[(oxan-4-yl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-(4-fluorophenyl)-N-(methanesulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-[4-(2-hydroxypropan-2-yl)piperidin-1-yl]-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-(4-fluorophenyl)-N-(methanesulfonyl)-4-[(oxan-4-yl)methoxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[4-(dimethylamino)piperidin-1-yl]-1-(4-fluorophenyl)-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-(4-fluorophenyl)-N-(methanesulfonyl)-4-(1′-methyl[4,4′-bipiperidin]-1-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[(1-acetylpiperidin-4-yl)methoxy]-1-(4-fluorophenyl)-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
methyl 4-({[1-(4-fluorophenyl)-6-[(methanesulfonyl)carbamoyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-h]pyridin-4-yl]oxy}methyl)piperidine-1-carboxylate;
3-cyclobutyl-N-(methanesulfonyl)-4-[2-(1-methylpiperidin-2-yl)ethoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-[(1,3-dimethoxypropan-2-yl)oxy]-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(methanesulfonyl)-4-{2-[(oxetan-3-yl)(propan-2-yl)amino]ethoxy}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[4-(cyanomethyl)-4-hydroxypiperidin-1-yl]-3-cyclobutyl-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-(4-azidophenyl)-N-(3-azidopropane-1-sulfonyl)-1-[3-(dimethylamino)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(methanesulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(methanesulfonyl)-1-phenyl-4-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(2-methoxyethanesulfonyl)-1-phenyl-4-[4-(2,2,2-trifluoroethyl) piperazin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(methanesulfonyl)-4-{4-[2-(morpholin-4-yl)ethyl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
rac-4-[(3aR,7aS)-1-acetyloctahydro-5H-pyrrolo[3, 2-c]pyridin-5-yl]-3-cyclobutyl-N-[3-(morpholin-4-yl)propane-1-sulfonyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(cyclopropanesulfonyl)-4-[(oxan-4-yl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(dimethylsulfamoyl)-4-[(oxan-4-yl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(ethanesulfonyl)-4-[(oxan-4-yl)methoxy]-1-phenyl-1H-pyrazolo[3,4-]pyridine-6-carboxamide;
N-(methanesulfonyl)-1-[2-(morpholin-4-yl)pyridin-4-yl]-4-[(oxan-4-yl)methoxy]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
ethyl 4-[1-(4-fluorophenyl)-6-[(methanesulfonyl)carbamoyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl]piperazine-1-carboxylate;
1-(4-fluorophenyl)-N-(methanesulfonyl)-4-(3-methyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-8-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-(4-fluorophenyl)-N-(methanesulfonyl)-3-(propan-2-yl)-4-[3-(trifluoromethyl) piperazin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-(4-fluorophenyl)-N-(methanesulfonyl)-4-[4-(2-methoxyethyl)piperazin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-(2,4-dioxo-1,3,8-triazaspiro[4.5]decan-8-yl)-1-(4-fluorophenyl)-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[4-(ethoxymethyl)-4-fluoropiperidin-1-yl]-1-(4-fluorophenyl)-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-{4-fluoro-4-[(2-methoxyethoxy)methyl]piperidin-1-yl}-1-(4-fluorophenyl)-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[(3R,4R)-3-fluoro-4-hydroxypiperidin-1-yl]-1-(4-fluorophenyl)-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[4-fluoro-4-(methoxymethyl)piperidin-1-yl]-1-(4-fluorophenyl)-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-{3-fluoro-3-[(2-methoxyethoxy)methyl]piperidin-1-yl}-1-(4-fluorophenyl)-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-[3-(morpholin-4-yl)propane-1-sulfonyl]-4-[(oxan-4-yl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-([1,4′-bipiperidin]-1-yl)-1-(4-fluorophenyl)-N-(methanesulfonyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-[(3R)-3-(hydroxymethyl)piperidin-1-yl]-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-[(3R)-3-(hydroxymethyl)piperidin-1-yl]-N-[3-(morpholin-4-yl)propane-1-sulfonyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-[(oxan-4-yl)methoxy]-1-phenyl-N-[4-(pyrrolidin-1-yl)piperidine-1-sulfonyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-[(2S)-2-(4-methylpiperazine-1-carbonyl)pyrrolidine-1-sulfonyl]-4-[(oxan-4-yl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-([1,4′-bipiperidine]-1-sulfonyl)-3-cyclobutyl-4-[(oxan-4-yl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-[methyl(propyl)sulfamoyl]-4-[(oxan-4-yl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-[ethyl(propyl)sulfamoyl]-4-[(oxan-4-yl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
ethyl 4-[({3-cyclobutyl-4-[(oxan-4-yl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carbonyl}sulfamoyl)amino]piperidine-1-carboxylate;
N-(4-acetyl-1,4-diazepane-1-sulfonyl)-3-cyclobutyl-4-[(oxan-4-yl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(morpholine-4-sulfonyl)-4-[(oxan-4-yl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-[4-(morpholin-4-yl)piperidine-1-sulfonyl]-4-[(oxan-4-yl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-[4-(4-methylpiperazine-1-carbonyl)piperidine-1-sulfonyl]-4-[(oxan-4-yl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(4-methylpiperazine-1-sulfonyl)-4-[(oxan-4-yl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(2-methylpropane-2-sulfonyl)-4-[(oxan-4-yl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-(4-azidophenyl)-N-(but-3-yne-1-sulfonyl)-1-[3-(dimethylamino)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(cyanomethanesulfonyl)-3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-([1,4′-bipiperidin]-1-yl)-3-cyclobutyl-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(2-hydroxyethanesulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(3-hydroxypropane-1-sulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-N-(piperidine-4-sulfonyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-N-(oxolane-3-sulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-(2,6-dimethylpyridin-4-yl)-N-(methanesulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-(1,1-dioxo-1λ6,4-thiazinan-4-yl)-N-(methanesufonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-N-[2-(1H-pyrazol-1-yl)ethanesulfonyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
benzyl [2-({3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carbonyl}sulfamoyl)ethyl]carbamate;
3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-N-(1-methylcyclopropane-1-sulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-N-(2-methylpropane-1-sulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
methyl ({3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carbonyl}sulfamoyl)acetate;
benzyl 3-({3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carbonyl}sulfamoyl)pyrrolidine-1-carboxylate;
tert-butyl 4-[1-(4-fluorophenyl)-6-[(methanesulfonyl)carbamoyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl]piperidine-1-carboxylate; and
3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-{4-[2-(methoxymethyl)morpholin-4-yl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(morpholine-4-sulfonyl)-1-phenyl-4-{4-[(pyrrolidin-1-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-(4-methoxy[1,4′-bipiperidin]-1-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-{4-[4-(propan-2-yl)piperazin-1-yl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(morpholine-4-sulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(2-amino-2-oxoethanesulfonyl)-3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(methanesulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1-(2-methoxypyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(2-acetamidoethanesulfonyl)-3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-N-(pyrrolidine-3-sulfonyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-N-[4-(pyrrolidin-1-yl)piperidine-1-sulfonyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-N-[(2S)-2-(4-methylpiperazine-1-carbonyl)pyrrolidine-1-sulfonyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-N-{4-[(2S)-2-(methoxymethyl) pyrrolidin-1-yl]piperidine-1-sulfonyl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-N-[methyl(propyl)sulfamoyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-[ethyl(propyl)sulfamoyl]-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
ethyl 4-[({3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carbonyl}sulfamoyl)amino]piperidine-1-carboxylate;
N-(4-acetyl-1,4-diazepane-1-sulfonyl)-3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-N-{4-[(2R)-2-(methoxymethyl) pyrrolidin-1-yl]piperidine-1-sulfonyl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-N-(morpholine-4-sulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-N-[4-(morpholin-4-yl)piperidine-1-sulfonyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-N-[4-(4-methylpiperazine-1-carbonyl)piperidine-1-sulfonyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(4-fluoropiperidine-1-sulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-N-(4-methylpiperazine-1-sulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(cyclopropanesulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(dimethylsulfamoyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(ethanesulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-cyclohexyl-N-(methanesulfonyl)-4-{4-[(morpholin-4-yl)methyl]phenyl}-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-cyclohexyl-N-(2-methoxyethanesulfonyl)-4-{4-[(morpholin-4-yl)methyl]phenyl}-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-cyclohexyl-N-(dimethylsulfamoyl)-4-{4-[(morpholin-4-yl)methyl]phenyl}-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-(4-fluorophenyl)-N-(2-methoxyethanesulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-{4-[(morpholin-4-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-(4-fluorophenyl)-N-(methanesulfonyl)-4-{4-[(morpholin-4-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-(4-fluorophenyl)-N-(methanesulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(ethanesulfonyl)-1-(4-fluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(cyclopropanesulfonyl)-1-(4-fluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-(4-fluorophenyl)-N-(2-methoxyethanesulfonyl)-4-{4-[2-(morpholin-4-yl)ethyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-{4-[2-(morpholin-4-yl)ethyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-[(1,4-dioxan-2-yl)methanesulfonyl]-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-cyclohexyl-N-(methanesulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-cyclohexyl-N-(2-methoxyethanesulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-cyclohexyl-N-(dimethylsulfamoyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-(4-fluorophenyl)-N-(methanesulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-cyclohexyl-N-(methanesulfonyl)-4-[4-(4-methylpiperazine-1-carbonyl)phenyl]-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-cyclohexyl-N-(dimethylsulfamoyl)-4-[4-(4-methylpiperazine-1-carbonyl)phenyl]-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-cyclohexyl-N-(dimethylsulfamoyl)-4-{4-[(morpholin-4-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-cyclohexyl-N-(dimethylsulfamoyl)-4-{4-[2-(morpholin-4-yl)ethyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-([1,4′-bipiperidin]-1-yl)-3-cyclobutyl-N-(dimethylsulfamoyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-([1,4′-bipiperidin]-1-yl)-3-cyclobutyl-N-(ethanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-([1,4′-bipiperidin]-1-yl)-3-cyclobutyl-N-(cyclopropanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-(4-fluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-N-(oxolane-3-sulfonyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(methanesulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1-(2-methylpyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-(4-fluorophenyl)-N-(methanesulfonyl)-4-{4-[2-(morpholin-4-yl)ethyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-[methyl(propyl)sulfamoyl]-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
ethyl 4-[({3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carbonyl}sulfamoyl)amino]piperidine-1-carboxylate;
3-cyclobutyl-N-(4-fluoropiperidine-1-sulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(1-methylcyclopropane-1-sulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(cyclopropanesulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(ethanesulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(2-methoxyethanesulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-{4-[(2S)-2-(methoxymethyl) pyrrolidin-1-yl]piperidine-1-sulfonyl}-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-{4-[1-(morpholin-4-yl)ethyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-cyclohexyl-N-(methanesulfonyl)-4-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-cyclohexyl-N-(dimethylsulfamoyl)-4-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-cyclohexyl-N-(dimethylsulfamoyl)-4-{4-[(piperidin-1-yl)methyl]phenyl}-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-cyclohexyl-N-(dimethylsulfamoyl)-3-[(propan-2-yl)oxy]-4-{4-[(pyrrolidin-1-yl)methyl]phenyl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-(4-fluorophenyl)-N-(methanesulfonyl)-4-{4-[1-(morpholin-4-yl)ethyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(ethanesulfonyl)-1-(4-fluorophenyl)-4-{4-[1-(morpholin-4-yl)ethyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-(4-fluorophenyl)-N-(2-methoxyethanesulfonyl)-4-{4-[(morpholin-4-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-(4-fluorophenyl)-N-(2-hydroxyethanesulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(chloromethanesulfonyl)-3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-([1,4′-bipiperidin]-1-yl)-3-cyclobutyl-1-(4-fluorophenyl)-N-(methanesulfonyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-([1,4′-bipiperidin]-1-yl)-3-cyclobutyl-1-(4-fluorophenyl)-N-(oxolane-3-sulfonyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-(4-fluorophenyl)-4-{4-[2-(morpholin-4-yl)ethyl]piperidin-1-yl}-N-(oxolane-3-sulfonyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-([1,4′-bipiperidine]-1-sulfonyl)-3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-([1,4′-bipiperidin]-1-yl)-3-cyclobutyl-N-[3-(morpholin-4-yl)propane-1-sulfonyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(4-methylpiperazine-1-sulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(dimethylsulfamoyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
ethyl 4-{[(3-cyclobutyl-1-phenyl-4-{4-[(pyrrolidin-1-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carbonyl)sulfamoyl]amino}piperidine-1-carboxylate;
3-cyclobutyl-N-{4-[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]piperidine-1-sulfonyl}-1-phenyl-4-{4-[(pyrrolidin-1-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(4-fluoropiperidine-1-sulfonyl)-1-phenyl-4-{4-[(pyrrolidin-1-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(4-methylpiperazine-1-sulfonyl)-1-phenyl-4-{4-[(pyrrolidin-1-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(1-methylcyclopropane-1-sulfonyl)-1-phenyl-4-{4-[(pyrrolidin-1-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(cyclopropanesulfonyl)-1-phenyl-4-{4-[(pyrrolidin-1-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(ethanesulfonyl)-1-phenyl-4-{4-[(pyrrolidin-1-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(2-methoxyethanesulfonyl)-1-phenyl-4-{4-[(pyrrolidin-1-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(2-methylpropane-2-sulfonyl)-1-phenyl-4-{4-[(pyrrolidin-1-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(ethanesulfonyl)-1-(4-fluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-(cyclobutyloxy)-1-cyclohexyl-4-{4-[(morpholin-4-yl)methyl]phenyl}-N-(oxolane-3-sulfonyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-cyclohexyl-N-(oxolane-3-sulfonyl)-4-[4-(pyridin-4-yl)piperazin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-cyclohexyl-N-(dimethylsulfamoyl)-4-[4-(pyridin-4-yl)piperazin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-cyclohexyl-N-(ethanesulfonyl)-4-[4-(pyridin-4-yl)piperazin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-(4-fluorophenyl)-N-[(2-methoxyethyl)(methyl)sulfamoyl]-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-([1,4′-bipiperidin]-1-yl)-3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(methanesulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1-[2-(oxan-4-yl)pyridin-4-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(methanesulfonyl)-1-(2-methoxypyridin-4-yl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-cyclohexyl-N-(dimethylsulfamoyl)-4-{4-[(morpholin-4-yl)methyl]phenyl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-cyclohexyl-N-(dimethylsulfamoyl)-4-{4-[2-(morpholin-4-yl)ethyl]phenyl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(but-3-yne-1-sulfonyl)-3-cyclobutyl-1-(4-fluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-([1,4′-bipiperidin]-1-yl)-3-cyclobutyl-N-(ethanesulfonyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-{4-[(1R)-1-(morpholin-4-yl)ethyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-{4-[(1S)-1-(morpholin-4-yl)ethyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-(cyclobutyloxy)-1-cyclohexyl-N-(dimethylsulfamoyl)-4-{4-[(morpholin-4-yl)methyl]phenyl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-(4-fluorophenyl)-N-[methyl(propan-2-yl)sulfamoyl]-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-[ethyl(methyl)sulfamoyl]-1-(4-fluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-(4-fluorophenyl)-N-(3-methoxyazetidine-1-sulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-(4-fluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-N-(pyrrolidine-1-sulfonyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-(4-fluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-N-(2,2,2-trifluoroethanesulfonyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-(4-fluorophenyl)-N-(morpholine-4-sulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-([1,4′-bipiperidin]-1-yl)-3-cyclobutyl-1-(4-fluorophenyl)-N-(2-methoxyethanesulfonyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(dimethylsulfamoyl)-1-[2-(morpholin-4-yl)pyridin-4-yl]-4-[(oxan-4-yl)methoxy]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(methanesulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-[2-(oxan-4-yl)pyridin-4-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-(4-fluorophenyl)-N-(2-hydroxyethanesulfonyl)-4-{4-[2-(morpholin-4-yl)ethyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
methyl 4-(1-{3-cyclobutyl-6-[(dimethylsulfamoyl)carbamoyl]-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridin-4-yl}piperidin-4-yl)piperazine-1-carboxylate;
4-[4-(4-acetylpiperazin-1-yl)piperidin-1-yl]-3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(ethanesulfonyl)-1-(4-fluorophenyl)-4-{4-[(morpholin-4-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-(4-fluorophenyl)-4-{4-[(morpholin-4-yl)methyl]piperidin-1-yl}-N-(oxolane-3-sulfonyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
ethyl 4-[1-(4-fluorophenyl)-6-[(methanesulfonyl)carbamoyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl]piperidine-1-carboxylate;
ethyl 4-{6-[(dimethylsulfamoyl)carbamoyl]-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl}piperidine-1-carboxylate;
3-cyclobutyl-N-(dimethylsulfamoyl)-1-(3-methylphenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(dimethylsulfamoyl)-1-(3-methoxyphenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(dimethylsulfamoyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-[4-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-[4-(ethoxymethyl)-4-fluoropiperidin-1-yl]-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-{4-fluoro-4-[(2-methoxyethoxy)methyl]piperidin-1-yl}-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-{3-fluoro-3-[(2-methoxyethoxy)methyl]piperidin-1-yl}-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-[4-fluoro-4-(methoxymethyl)piperidin-1-yl]-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(4-cyanopiperidine-1-sulfonyl)-3-cyclobutyl-1-(4-fluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-(4-fluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-N-(oxetane-3-sulfonyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(cyclopropanesulfonyl)-1-(4-fluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-(4-fluorophenyl)-N-(1-methylcyclopropane-1-sulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(methanesulfonyl)-1-(3-methylphenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(methanesulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-[4-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluoro-3-methylphenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(dimethylsulfamoyl)-1-(3-fluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(dimethylsulfamoyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-(4-fluoro-3-methylphenyl)-N-(methanesulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-(3-fluorophenyl)-N-(methanesulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(methanesulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-(4-fluorophenyl)-N-(methylsulfamoyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-(4-fluorophenyl)-N-(methanesulfonyl)-4-[(4-methylpiperazin-1-yl)methyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-(4-fluorophenyl)-N-(methanesulfonyl)-4-[(morpholin-4-yl)methyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-[(morpholin-4-yl)methyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-{[4-(methoxymethyl)piperidin-1-yl]methyl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-(4-cyano[1,4′-bipiperidin]-1-yl)-3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[4-(3-cyanoazetidin-1-yl)piperidin-1-yl]-3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-[4-(3-methoxypyrrolidin-1-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(dimethylsulfamoyl)-4-(4-fluoro[1,4′-bipiperidin]-1-yl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-(4,4-difluoro[1,4′-bipiperidin]-1-yl)-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[4-(2-cyanomorpholin-4-yl)piperidin-1-yl]-3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-{4-[methyl(oxan-4-yl)amino]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(dimethylsulfamoyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-{2-[(propan-2-yl)oxy]pyridin-4-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(methanesulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-{2-[(propan-2-yl)oxy]pyridin-4-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(dimethylsulfamoyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1-[2-(oxan-4-yl)pyridin-4-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-[4-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-[3-(morpholin-4-yl)-1-oxa-8-azaspiro[4.5]decan-8-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-cyclohexyl-N-(dimethylsulfamoyl)-3-[(propan-2-yl)oxy]-4-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-cyclohexyl-N-(dimethylsulfamoyl)-4-[4-(2-methylpyridin-4-yl)piperazin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-cyclohexyl-4-[6-(4-cyclopropylpiperazin-1-yl)pyridin-3-yl]-N-(dimethylsulfamoyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-(4-fluorophenyl)-N-(3-fluoropyrrolidine-1-sulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-(4-fluorophenyl)-N-(3-methoxypyrrolidine-1-sulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-3-cyclobutyl-N-(dimethylsulfamoyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-(4-fluorophenyl)-N-[4-(methoxymethyl)piperidine-1-sulfonyl]-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-[4-(3-fluoropyrrolidin-1-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-cyclohexyl-N-(dimethylsulfamoyl)-4-{6-[4-(propan-2-yl)piperazin-1-yl]pyridin-3-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-cyclohexyl-N-(dimethylsulfamoyl)-4-{4-[1-(morpholin-4-yl)ethyl]phenyl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-cyclohexyl-4-{4-[4-(dimethylamino)piperidine-1-carbonyl]phenyl}-N-(methanesulfonyl)-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-cyclohexyl-4-{4-[4-(dimethylamino)piperidine-1-carbonyl]phenyl}-N-(2-methoxyethanesulfonyl)-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-cyclohexyl-4-{4-[4-(dimethylamino)piperidine-1-carbonyl]phenyl}-N-(dimethylsulfamoyl)-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-cyclohexyl-N-(dimethylsulfamoyl)-4-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-(4-fluorophenyl)-N-(methanesulfonyl)-4-(4-methoxy[1,4-bipiperidin]-1-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-[4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl]-N-(dimethylsulfamoyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(cyclopropanesulfonyl)-4-[4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-cyclohexyl-N-(dimethylsulfamoyl)-4-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-cyclohexyl-N-(dimethylsulfamoyl)-4-{6-[4-(2-methoxyethyl)piperazin-1-yl]pyridin-3-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-cyclohexyl-N-(dimethylsulfamoyl)-4-{4-[4-(propan-2-yl)piperazin-1-yl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-[4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl]-N-[methyl(propyl)sulfamoyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-[4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl]-N-(morpholine-4-sulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-[4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl]-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-[4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl]-N-(1-methylcyclopropane-1-sulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-[4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl]-N-(methylsulfamoyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-cyclohexyl-4-[4-(4-cyclopropylpiperazin-1-yl)phenyl]-N-(dimethylsulfamoyl)-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-{4-[3-(trifluoromethyl)pyrrolidin-1-yl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[4-(3-cyanopyrrolidin-1-yl)piperidin-1-yl]-3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-(3-cyano[1,4′-bipiperidin]-1-yl)-3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(dimethylsulfamoyl)-4-(3-fluoro[1,4′-bipiperidin]-1-yl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-(4-fluorophenyl)-N-(methanesulfonyl)-4-{4-[3-(trifluoromethyl) pyrrolidin-1-yl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[4-(3-cyanopyrrolidin-1-yl)piperidin-1-yl]-3-cyclobutyl-1-(4-fluorophenyl)-N-(methanesulfonyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-(3-cyano[1,4′-bipiperidin]-1-yl)-3-cyclobutyl-1-(4-fluorophenyl)-N-(methanesulfonyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-(3-fluoro[1,4′-bipiperidin]-1-yl)-1-(4-fluorophenyl)-N-(methanesulfonyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-(4-fluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-N-(piperidine-1-sulfonyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(3-fluoroazetidine-1-sulfonyl)-1-(4-fluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-[4-(3-methoxyazetidin-1-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-[3-(trifluoromethyl)[1,4′-bipiperidin]-1′-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-(3-methoxy[1,4′-bipiperidin]-1-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-[4-(2,2-dimethylmorpholin-4-yl)piperidin-1-yl]-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(2-acetamidoethanesulfonyl)-3-cyclobutyl-1-(4-fluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-[2-(difluoromethoxy)pyridin-4-yl]-N-(dimethylsulfamoyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(azetidine-1-sulfonyl)-3-cyclobutyl-1-(4-fluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-(4-fluorophenyl)-N-[(2R)-2-(methoxymethyl)pyrrolidine-1-sulfonyl]-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-(4-fluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-N-[(oxan-4-yl)sulfamoyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-(4-fluorophenyl)-N-[methyl(oxan-4-yl)sulfamoyl]-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(3,3-difluoroazetidine-1-sulfonyl)-1-(4-fluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[(3S)-4-benzyl-3-methylpiperazin-1-yl]-3-cyclobutyl-1-cyclohexyl-N-(dimethylsulfamoyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[(3R)-4-benzyl-3-methylpiperazin-1-yl]-3-cyclobutyl-1-cyclohexyl-N-(dimethylsulfamoyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-[4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl]-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-(9-cyclopropyl-3,9-diazaspiro[5.5]undecan-3-yl)-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-(4-fluorophenyl)-N-(methanesulfonyl)-4-[4-(3-methoxyazetidin-1-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-(4-fluorophenyl)-N-(methanesulfonyl)-4-[3-(trifluoromethyl)[1,4′-bipiperidin]-1′-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-(4-fluorophenyl)-N-(methanesulfonyl)-4-(3-methoxy[1,4-bipiperidin]-1-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-[4-(2,2-dimethylmorpholin-4-yl)piperidin-1-yl]-1-(4-fluorophenyl)-N-(methanesulfonyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-{4-[(pyrrolidin-1-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
ethyl 4-(1-{3-cyclobutyl-6-[(dimethylsulfamoyl)carbamoyl]-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridin-4-yl}piperidin-4-yl)piperazine-1-carboxylate;
3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-{4-[(2-methoxyethyl)(methyl)amino]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-(4-fluorophenyl)-N-(methoxysulfamoyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-[1-(4,4-difluorocyclohexyl)piperidin-4-yl]-1-(4-fluorophenyl)-N-(methanesulfonyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-[1-(4,4-difluorocyclohexyl)piperidin-4-yl]-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-{[4-(morpholin-4-yl)piperidin-1-yl]methyl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-(4-fluorophenyl)-N-(methanesulfonyl)-4-{[4-(morpholin-4-yl)piperidin-1-yl]methyl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-cyclohexyl-4-{4-[(4-cyclopropylpiperazin-1-yl)methyl]phenyl}-N-(methanesulfonyl)-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-[1-(propan-2-yl)piperidin-4-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-(4-fluorophenyl)-N-(methanesulfonyl)-4-[1-(oxan-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-(4-fluorophenyl)-N-(methanesulfonyl)-4-{1-[(oxan-4-yl)methyl]piperidin-4-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-{1-[(oxan-4-yl)methyl]piperidin-4-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-{1-[(2,5-dimethoxyoxolan-3-yl)methyl]piperidin-4-yl}-1-(4-fluorophenyl)-N-(methanesulfonyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-(4-fluorophenyl)-N-(methanesulfonyl)-4-[1-(3,3,3-trifluoropropyl)piperidin-4-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-[1-(3,3,3-trifluoropropyl)piperidin-4-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-(4-hydroxy[1,4′-bipiperidin]-1-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
methyl {3-cyclobutyl-1-(4-fluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carbonyl}sulfamate;
3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-{4-[4-(2-methoxyethyl)piperazin-1-yl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-(4-fluorophenyl)-4-[4-(methoxymethyl)piperidin-1-yl]-N-[3-(morpholin-4-yl)pyrrolidine-1-sulfonyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(4-cyclopropylpiperazine-1-sulfonyl)-1-(4-fluorophenyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-(4-fluorophenyl)-N-[4-(2-methoxyethyl)piperazine-1-sulfonyl]-4-[4-(methoxymethyl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-(4-fluorophenyl)-N-(methanesulfonyl)-4-[1-(propan-2-yl)piperidin-4-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-[1-(oxan-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-[1-(cyclopropylmethyl)piperidin-4-yl]-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-[9-(oxetan-3-yl)-3,9-diazaspiro[5.5]undecan-3-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-{4-[4-(oxetan-3-yl)piperazin-1-yl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-[(1-cyclopropylpiperidin-4-yl)methoxy]-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-[(1-cyclobutylpiperidin-4-yl)methoxy]-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-[(1-cyclohexylpiperidin-4-yl)methoxy]-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-{[1-(oxan-4-yl)piperidin-4-yl]methoxy}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-{1-[(2,5-dimethoxyoxolan-3-yl)methyl]piperidin-4-yl}-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(dimethylsulfamoyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-{2-[(propan-2-yl)oxy]pyrimidin-4-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(dimethylsulfamoyl)-1-(2-ethoxypyrimidin-4-yl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)-N-(dimethylsulfamoyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-(4-fluorophenyl)-N-(4-methylpiperazine-1-sulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-[1-(propan-2-yl)octahydro-5H-pyrrolo[3, 2-c]pyridin-5-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-(1-cyclobutyloctahydro-5H-pyrrolo[3, 2-c]pyridin-5-yl)-N-(dimethylsufamoyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-[1-(oxetan-3-yl)octahydro-5H-pyrrolo[3, 2-c]pyridin-5-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-[1-(oxan-4-yl)octahydro-5H-pyrrolo[3, 2-c]pyridin-5-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-(4-fluorophenyl)-4-(4-methoxy[1,4′-bipiperidin]-1-yl)-N-(methylsulfamoyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-(4-fluorophenyl)-4-(4-methoxy[1,4′-bipiperidin]-1-yl)-N-sulfamoyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-cyclohexyl-4-[4-(hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carbonyl)phenyl]-N-(methanesulfonyl)-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(azetidine-1-sulfonyl)-3-cyclobutyl-1-(4-fluorophenyl)-4-(4-methoxy[1,4′-bipiperidin]-1-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-cyclohexyl-4-(4-{[3-(dimethylamino)azetidin-1-yl]methyl}phenyl)-N-(methanesulfonyl)-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-cyclohexyl-N-(methanesulfonyl)-3-[(propan-2-yl)oxy]-4-(4-{[4-(propan-2-yl)piperazin-1-yl]methyl}phenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-cyclohexyl-N-(methanesulfonyl)-4-{4-[(4-methoxypiperidin-1-yl)methyl]phenyl}-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-cyclohexyl-N-(methanesulfonyl)-4-{4-[(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methyl]phenyl}-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-cyclohexyl-N-(methanesulfonyl)-4-[4-(5-methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carbonyl)phenyl]-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-(4-fluorophenyl)-N-(methylsulfamoyl)-4-{4-[4-(propan-2-yl)piperazin-1-yl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
4-[4-(4-cyano-1-methylpiperidin-4-yl)phenyl]-1-cyclohexyl-N-(methanesulfonyl)-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-cyclohexyl-4-{4-[3-(dimethylamino)azetidine-1-carbonyl]phenyl}-N-(methanesulfonyl)-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-cyclohexyl-N-(methanesulfonyl)-4-{4-[(8-methyl-2-oxa-5,8-diazaspiro[3.5]nonan-5-yl)methyl]phenyl}-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-cyclohexyl-4-{4-[(4-ethylpiperazin-1-yl)methyl]phenyl}-N-(methanesulfonyl)-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-cyclohexyl-4-(4-{[4-(dimethylamino)piperidin-1-yl]methyl}phenyl)-N-(methanesulfonyl)-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
1-(4-fluorophenyl)-N-(methanesulfonyl)-4-(4-methoxy[1,4′-bipiperidin]-1′-yl)-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-(4-fluorophenyl)-N-(3-methoxyazetidine-1-sulfonyl)-4-(4-methoxy[1,4′-bipiperidin]-1′-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(3-fluoroazetidine-1-sulfonyl)-1-(4-fluorophenyl)-4-(4-methoxy[1,4′-bipiperidin]-1′-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-(4-fluorophenyl)-4-(4-methoxy[1,4′-bipiperidin]-1-yl)-N-(morpholine-4-sulfonyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(methanesulfonyl)-4-[4-(morpholin-4-yl)cyclohexyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(dimethylsulfamoyl)-4-[4-(morpholin-4-yl)cyclohexyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-4-(4-fluoro[1,4′-bipiperidin]-1-yl)-1-(4-fluorophenyl)-N-(methylsulfamoyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
N-(azetidine-1-sulfonyl)-3-cyclobutyl-1-(4-fluorophenyl)-4-{4-[4-(propan-2-yl)piperazin-1-yl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-[3-(difluoromethoxy)phenyl]-N-(dimethylsulfamoyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-(4-fluorophenyl)-N-(methanesulfonyl)-N-methyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(methanesulfonyl)-N-methyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(methanesulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-N-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(ethanesulfonyl)-N-methyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-N-(ethanesulfonyl)-N-methyl-1-phenyl-4-{4-[(pyrrolidin-1-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
2-(3-cyclobutyl-1-phenyl-4-{4-[(pyrrolidin-1-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carbonyl)-6-methy-1λ6,2,6-thiadiazinane-1,1-dione;
2-(3-cyclobutyl-1-phenyl-4-{4-[(pyrrolidin-1-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carbonyl)-1λ6,2-thiazolidine-1,1-dione;
3-cyclobutyl-N-(methanesulfonyl)-N-methyl-1-phenyl-4-{4-[(pyrrolidin-1-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
2-(3-cyclobutyl-1-phenyl-4-{4-[(pyrrolidin-1-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carbonyl)-1λ6,2-thiazinane-1,1-dione;
2-{3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carbonyl}-6-methyl-1λ6,2,6-thiadiazinane-1,1-dione;
2-{3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carbonyl}-1λ6,2-thiazolidine-1,1-dione;
2-{3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carbonyl}-1λ6,2-thiazinane 1,1-dione;
2-{3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carbonyl}-1λ6,2-thiazolidine-1,1-dione;
2-{3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carbonyl}-1λ6,2-thiazinane-1,1-dione;
3-cyclobutyl-1-(4-fluorophenyl)-4-[4-(methoxymethyl)piperidin-1-yl]-N-(methylsulfamoyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-(4-fluorophenyl)-N-(2-methoxyethanesulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-(4-fluorophenyl)-4-[4-(methoxymethyl)piperidin-1-yl]-N-(morpholine-4-sulfonyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-(4-fluorophenyl)-N-(3-hydroxypropane-1-sulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
ethyl 4-[({3-cyclobutyl-1-(4-fluorophenyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carbonyl}sulfamoyl)amino]piperidine-1-carboxylate;
3-cyclobutyl-1-(4-fluorophenyl)-4-[4-(methoxymethyl)piperidin-1-yl]-N-[(oxetan-3-yl)sulfamoyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-(4-fluorophenyl)-4-[4-(methoxymethyl)piperidin-1-yl]-N-[(oxan-4-yl)sulfamoyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
3-cyclobutyl-1-(4-fluorophenyl)-4-[4-(methoxymethyl)piperidin-1-yl]-N-[4-(morpholin-4-yl)piperidine-1-sulfonyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
ethyl 4-{3-cyclobutyl-1-(4-fluorophenyl)-6-[(2-methoxyethanesulfonyl)carbamoyl]-1H-pyrazolo[3,4-b]pyridin-4-yl}piperazine-1-carboxylate;
ethyl 4-{3-cyclobutyl-1-(4-fluorophenyl)-6-[(morpholine-4-sulfonyl)carbamoyl]-1H-pyrazolo[3,4-b]pyridin-4-yl}piperazine-1-carboxylate;
ethyl 4-{3-cyclobutyl-1-(4-fluorophenyl)-6-[(methanesulfonyl)carbamoyl]-1H-pyrazolo[3,4-b]pyridin-4-yl}piperazine-1-carboxylate;
ethyl 4-{3-cyclobutyl-1-(4-fluorophenyl)-6-[(methylsulfamoyl)carbamoyl]-1H-pyrazolo[3,4-b]pyridin-4-yl}piperazine-1-carboxylate;
2-methylpropyl 4-{3-cyclobutyl-1-(4-fluorophenyl)-6-[(methanesulfonyl)carbamoyl]-1H-pyrazolo[3,4-b]pyridin-4-yl}piperazine-1-carboxylate;
2-methylpropyl 4-{3-cyclobutyl-1-(4-fluorophenyl)-6-[(morpholine-4-sulfonyl)carbamoyl]-1H-pyrazolo[3,4-b]pyridin-4-yl}piperazine-1-carboxylate;
2-methylpropyl 4-{3-cyclobutyl-1-(4-fluorophenyl)-6-[(2-methoxyethanesulfonyl)carbamoyl]-1H-pyrazolo[3,4-b]pyridin-4-yl}piperazine-1-carboxylate;
2-methylpropyl 4-{3-cyclobutyl-1-(4-fluorophenyl)-6-[(methylsulfamoyl)carbamoyl]-1H-pyrazolo[3,4-b]pyridin-4-yl}piperazine-1-carboxylate;
3-cyclobutyl-1-(4-fluorophenyl)-4-(9-methyl-3,9-diazaspiro[5.5]undecan-3-yl)-N-(morpholine-4-sulfonyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide; and
N-(2-aminopyridine-3-sulfonyl)-3-cyclobutyl-1-(4-fluorophenyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide.

33. A pharmaceutical composition comprising compound of claim 1, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.

34. A method for treating cystic fibrosis in a subject comprising administering a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

35. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, one potentiator, and one or more additional correctors.

36. A method for treating cystic fibrosis in a subject comprising administering a compound of claim 1 or a pharmaceutically acceptable salt thereof, one potentiator, and one or more additional correctors, to a subject in need thereof.

37. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents.

38. The pharmaceutical composition of claim 37 wherein the additional therapeutic agents are selected from the group consisting of CFTR modulators and CFTR amplifiers.

39. The pharmaceutical composition of claim 37 wherein the additional therapeutic agents are CFTR modulators.

40. A method for treating cystic fibrosis in a subject comprising administering a compound of claim 1 or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents.

41. The method of claim 40 wherein the additional therapeutic agents are selected from the group consisting of CFTR modulators, corrected CFTR stabilizers and CFTR amplifiers.

42. The method of claim 40 wherein the additional therapeutic agents are CFTR modulators.

43. benzyl 3-({3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carbonyl }sulfamoyl)pyrrolidine- 1-carboxylate.

44. 3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-{4-[2-(methoxymethyl)morpholin-4-yl]piperidin-1-yl }-1H-pyrazolo[3,4-b]pyridine-6-carboxamide.

45. 3-cyclobutyl-N-(morpholine-4-sulfonyl)-1-phenyl-4-{4-[(pyrrolidin-1-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide.

46. 3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-(4-methoxy [1,4′-bipiperidin]-1′-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide.

47. 3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-{4-[4-(propan-2-yl)piperazin-1-yl]piperidin-1-yl }-1H-pyrazolo[3,4-b]pyridine-6-carboxamide.

48. 3-cyclobutyl-N-(morpholine-4-sulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide.

49. 3-cyclobutyl-N-(methanesulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1-(2-methoxypyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide.

50. N-(2-acetamidoethanesulfonyl)-3 -cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide.